Condensed pyrazole derivatives, process for producing the same and use thereof

ABSTRACT

Novel pharmaceutical compositions for inhibiting Th2-selective immune response and pharmaceutical compositions for inhibiting cyclooxygenase comprising condensed pyrazole derivatives represented by the general formula (I):  
                 
 
     or salts thereof.

FIELD OF THE INVENTION

[0001] The present invention relates to a novel condensed pyrazolederivative, which is useful as a preventive and/or therapeutic agent fordiseases caused by immune malfunction and accompanied by immunemalfunction, and for graft rejection and graft versus host diseasesassociated with transplantation of organs and bone marrow, and which hasexcellent anti-inflammatory and analgesic and antipyretic activities, aprocess for producing the same, and the use thereof.

BACKGROUND ART

[0002] Mosmann et al., proposed that helper T cells (Th), lymphocytesplaying a central role in immune responses, could be classified into twosubsets, Th1 and Th2 cells, according to secretion patterns of cytokines[J. Immunol., vol.136, p.2348 (1986)]. Since then, several reportsindicating that abnormality in the balance of Th1 and Th2 cells isclosely involved in onset and aggravation of diseases caused by immunemalfunction such as allergic diseases and autoimmune diseases and ofdiseases associated with immune malfunction have been published [MedicalImmunology, vol.15, p.401 (1988); Annual Review of Immunology, vol.12,p.227 (1994); and Immunology Today, vol.17, p.138 (1996)].

[0003] Among the diseases above, allergic diseases are believed to becaused mainly by an increase in the number and the accentuation of Th2cells, and an increase in production of IgE antibodies, IL-4 and IL-5are said to be one of the aggravation factors. IL-4, one of cytokinesproduced in Th2 cell, accelerates production of IgE antibodies, whileIL-5 accelerates differentiation, proliferation and migration ofacidocytes, and also has a life-extending effect on the cells.Therefore, a medicine to suppress the functions of Th2 cell has apotential to relieve symptoms of the allergic diseases. Antiallegicdrugs currently available, mainly suppressing immediate allergicresponses, are not so effective for late-onset allergic diseases such assevere asthma and atopic dermatitis in the allergic diseases. Steroiddrugs are often used for that purpose, but various side effectsassociated with taking such drugs for a long period of time (such assteroid skin diseases, adrenal cortical incompetence, etc.) are cited asthe disadvantage.

[0004] Additionally, cyclosporin and tacrolimus are also used as theimmunosuppressive drugs, but these drugs are non-specific, i.e.,suppressing immune responses of Th2 side as well as Th1 side, and thusthe administration thereof often lead to deterioration in resistance toinfection and cause severe side effects such as nephrotoxicity andhepatotoxicity. Condensed heterocyclic compounds having suppressiveactivities to the Th2 immune responses have been described in JP10-298181 A, JP 10-324631 A, JP 10-330369 A, WO98/47899 and J. Immunol.,162, 7470 (1999), but hitherto, no condensed pyrazole derivatives havingthe suppressive activity to the Th2 immune responses have been reported.

[0005] Pyrazolo[3,4-b]pyridine derivatives relevant to the presentinvention have been described in JP 48-57995 A (1973), JP 48-81891 A,U.S. Pat. No. 3,840,546 (1974), and Arch. Pharma., vol.307, p.117(1974).

[0006] Non-steroidal anti-inflammatory drugs (NSAIDs) have been widelyused for treatment of the inflammatory diseases such as inflammation,pain, fever, but these drugs also have clinical disadvantage in thatthey are not free from the side effect of gastrointestinal disordersadequately.

[0007] Recently, a hypothesis that cyclooxygenase (COX), the site ofaction of the non-steroidal anti-inflammatory agents, has two isozymes,COX-1 and COX-2, and inhibition of the COX-1, the constitutive enzymethereof, could trigger gastrointestinal disorders was proposed. Sincethen, development of a COX-2 selective inhibitor has been intensivelycarried out to overcome the problems of gastrointestinal disorders.Consequently, Celecoxib and Rofecoxib are brought on the market in 1999,from Searle and Merck respectively, as NSAIDs that have fewer problemsof the gastrointestinal disorders. But, a fact that a COX-1 knock-outmouse does not have gastric disorder was pointed out, for example, inCell, vol.83, p.483 (1995), and a fact that even the COX-1 selectiveinhibitors have fewer cases of stomach disorders if they do not induceapoptosis of the gastric mucosal cells was also reported in Eur. J.Pharm., vol.380, p.271 (1998), and thus there is still doubt in that theCOX-2 selective inhibitor can completely conquer the problem of thegastrointestinal disorders.

DISCLOSURE OF THE INVENTION

[0008] An object of the present invention is to provide a novelTh2-selective immune response suppressant which can be used, effectivelyand with fewer side effects, for prevention and/or treatment of allergicdiseases by selectively suppressing Th2 side immune responses typifiedby production of cytokines such as IL-4 and 1L-5 and IgE antibodies bothof which are involved in the allergic responses, and by controlling thebalance of Th1 and Th2 cells.

[0009] As described above, the conventional NSAIDs have potent medicinalactivities, but also the inevitable problem of gastrointestinaldisorders, and thus had a disadvantage in that the administrationthereof to a patient over a long period of time or to the elderly wasdifficult. Development of a novel compound satisfactory as the drug forthe diseases described above has been highly desired. On the other hand,development of a new COX inhibitor, having no carboxyl groupscharacteristic in the conventional NSAIDs, and thus having a basicchemical structure completely different from those of the conventionalanti-inflammatory drugs, is also desirable since the COX inhibitor has apotential to be a drug having excellent anti-inflammatory, analgesic andantipyretic actions and having fewer problems of gastrointestinaldisorders.

[0010] Another object of the present invention is to develop such a COXinhibitor.

[0011] After an intensive study, the present inventors have found that acondensed pyrazole derivative represented by the formula (I):

[0012] wherein, R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted, or acarboxyl group which may be optionally esterified or amidated; R² isunsubstituted, or a hydrogen atom or a hydrocarbon group which may beoptionally substituted; R³ is a heterocyclic group which may beoptionally substituted; X, Y, and Z are, respectively, hydrogen,halogen, nitrile, a hydrocarbon group which may be optionallysubstituted, a carboxyl group which may be esterified or amidated, anacyl group which may be optionally substituted, —NR⁴R⁵, an oxygen atom,OR⁴, a sulfur atom, or SR⁴ (R⁴ and R⁵ are, respectively, a hydrogenatom, a hydrocarbon group which may be optionally substituted, or aheterocyclic group which may be optionally substituted, or may bind eachother to form a cyclic amino group or a heterocyclic group with thenitrogen bound thereto), or X and Y may bind each other to form ring A,or Y and Z may bind each other to form ring B; bond portions indicatedby both solid and broken lines are, respectively, a single bond or adouble bond, and bond portions indicated by a broken line are,respectively, a single bond or unsubstituted; ring A is a homocyclic orheterocyclic 5- to 7-membered ring which may be optionally substituted;ring B is a homocyclic or heterocyclic 5- to 7-membered ring which maybe optionally substituted; and n is an integer of 0 or 1, or a saltthereof suppresses selectively the Th2 side immune responses byinhibiting production of cytokines such as IL-4 and IL-5 and theproduction of IgE antibodies, but has no influence on IFN-γ, a cytokineof Th1 side, and on the basis of the finding, the present invention wascompleted after further studies.

[0013] The present invention provides a pharmaceutical composition forselectively suppressing the Th2 immune responses comprising a condensedpyrazole derivative represented by the formula (I) [hereinafter,occasionally referred to as compound (I)] or a salt thereof. Thepharmaceutical composition of the present invention is useful,especially, as a preventive and/or therapeutic agent for diseases causedby immune malfunction or associated with immune malfunction, as apreventive and/or therapeutic agent for graft rejection, as a preventiveand/or therapeutic agent for graft versus host diseases, as a preventiveand/or therapeutic agent for allergic diseases, and as a regulator ofTh1/Th2 balance.

[0014] The present invention also provides a process for producing anovel compound, a condensed pyrazole derivative, represented by theformula (I′):

[0015] wherein, R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted, or acarboxyl group which may be optionally esterified or amidated; R² isunsubstituted, a hydrogen atom, or a hydrocarbon group which may beoptionally substituted; R³′ is an unsaturated heterocyclic group havingonly a nitrogen atom as the hetero atom, which may be optionallysubstituted; X′, Y′, and Z′ are respectively, hydrogen, halogen,nitrile, a hydrocarbon group which may be optionally substituted, acarboxyl group which may be optionally esterified or amidated, an acylgroup which may be optionally substituted, —CON₃, —NR⁴R⁵, ═N—N═R⁴ , —N₃,an oxygen atom, —OR⁴, a sulfur atom, or —SR⁴ (R⁴ and R⁵ are,respectively, a hydrogen atom, a hydrocarbon group which may beoptionally substituted, a heterocyclic group which may be optionallysubstituted, or may bind each other to form a cyclic amino group or aheterocyclic group with the nitrogen bound thereto), or X′ and Y′ maybind each other to form ring A′, while one of X′ and Z′ is an oxygenatom or —OR⁴; bond portions indicated by solid and broken lines are,respectively, a single bond or a double bond, and a bond portionindicated by a broken line is a single bond or unsubstituted; and ringA′ is a homocyclic or heterocyclic 5- to 7-membered ring which may beoptionally substituted [hereinafter, occasionally referred to ascompound (I′)], or a salt thereof, useful as an active component for thepharmaceutical compositions described above or an intermediate for theproduction thereof.

[0016] Additionally, after an intensive study, the present inventorshave found that a compound (J) or a salt thereof, especially, apyrazoloquinoline derivative represented by the formula:

[0017] wherein, R^(1a) is a hydrogen atom, a hydrocarbon group which maybe optionally substituted, or a carboxyl group which may be optionallyesterified or amidated; R^(2a) is unsubstituted, a hydrogen atom, or ahydrocarbon group which may be optionally substituted; R^(3a) is aheterocyclic group which may be optionally substituted; X^(a) ishydrogen, halogen, nitrile, a hydrocarbon group which may be optionallysubstituted, a carboxyl group which may be optionally esterified oramidated, an acyl group which may be optionally substituted,—NR^(4a)R^(5a), an oxygen atom , —OR^(4a), a sulfur atom, or —SR^(4a)(R^(4a) and R^(5a) are, respectively, a hydrogen atom, a hydrocarbongroup which may be optionally substituted, or may bind each other toform a cyclic amino group or a heterocyclic group with the nitrogen atombound thereto); bond portions indicated by solid and broken lines are,respectively, a single bond or a double bond, and bond portionsindicated by a broken line are, respectively, a single bond orunsubstituted; B^(a) ring is a homocyclic or heterocyclic 5- to7-membered ring which may be optionally substituted; and m is an integerof 0 or 1, or a salt thereof has the desired COX inhibition activity,and the present invention was completed.

[0018] Meanwhile, a pyrazoloquinoline derivative represented by theformula:

[0019] was described to have an analgesic activity in Monatsh. Chem.,vol.128, p.85 (1997).

[0020] Therefore, the present invention provides a pharmaceuticalcomposition comprising a pyrazole derivative represented by the formula(I) or a salt thereof, useful as a pharmaceutical composition forinhibiting COX, especially as a preventive and/or therapeutic agent ofinflammatory diseases, as a preventive and/or therapeutic agent ofarthritis, as a preventive and/or therapeutic agent of rheumatism, andas a preventive and/or therapeutic agent of chronic rheumatoidarthritis.

[0021] A pyrazoloquinoline derivative represented by the formula (Ia′):

[0022] wherein, R^(1a) is a hydrogen atom, a hydrocarbon group which maybe optionally substituted, or a carboxyl group which may be optionallyesterified or amidated; R^(2a) is unsubstituted, a hydrogen atom, or ahydrocarbon group which may be optionally substituted; R^(3ab) is anunsaturated heterocyclic group having 2 or less nitrogen atoms as thehetero atoms which may be optionally substituted, or an unsaturatedmonocyclic heterocyclic group having a nitrogen atom and a sulfur atomas the hetero atoms; X^(a) is hydrogen, halogen, nitrile and ahydrocarbon group which may be optionally substituted, a carboxyl groupwhich may be optionally esterified or amidated, an acyl group which maybe optionally substituted, —NR^(4a)R^(5a), an oxygen atom, —OR^(4a), asulfur atom, or —SR^(4a) (R^(4a) and R^(5a) are, respectively, ahydrogen atom, a hydrocarbon group which may be optionally substituted,or may bind each other to form a cyclic amino group or a heterocyclicgroup with the nitrogen atom bound thereto); bond portions indicated bysolid and broken lines are, respectively, a single bond or a doublebond, and bond portions indicated by a broken line are, respectively, asingle bond or unsubstituted; ring B^(a) is a homocyclic or heterocyclic5- to 7-membered ring which may be optionally substituted; and m is aninteger of 0 or 1, or a salt thereof is a novel compound that has notbeen described in literature. The present invention also provides aprocess for producing the novel pyrazoloquinoline derivative representedby the formula (Ia′) or the salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0023] Each of the condensed pyrazole derivatives represented byformulas (I), (I′), (Ia), and (Ia′) may be present as forms of variousisomers, but it should be construed that both isolated isomers andmixture of isomers are included in the compounds represented by formulas(I), (I′), (Ia), and (Ia′) in the present specification.

[0024] The terms, “Th1” and “Th2”, indicate, respectively, “type 1helper T cell” and “type 2 helper T cell” in the present specification.

[0025] The “hydrocarbon groups”, in the phrase “a hydrocarbon groupwhich may be optionally substituted” used in the present specification,are, for example, an aliphatic hydrocarbon group, a saturated monocyclichydrocarbon group, an aromatic hydrocarbon group, etc., preferably thegroup having 1 to 16 carbons. More specifically, examples of thehydrocarbon group are alkyl groups, alkenyl groups, alkynyl groups,cycloalkyl groups, and aryl groups, etc.

[0026] Preferred examples of “the alkyl group” include a lower alkylgroup or the like, more specifically, C₁₋₆ alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl,pentyl, hexyl, etc.

[0027] Preferred examples of “the alkenyl group” are lower alkenylgroups or the like, more specifically C₂₋₆ alkenyl groups such as vinyl,1-propenyl, allyl, isopropenyl, butenyl, and isobutenyl, etc.

[0028] Preferred examples of “the alkynyl group” are lower alkynylgroups or the like, more specifically a C₂₋₆ alkynyl group such asethynyl, propargyl, and 1-propynyl, etc.

[0029] Preferred examples of “the cycloalkyl group” are lower cycloalkylgroups or the like, more specifically C₃₋₆ cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, etc.

[0030] Preferred examples of “the aryl group” are C₆₋₁₄ aryl groups orthe like, such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-indenyl,and 2-anthryl, etc., more preferably phenyl group, etc.

[0031] Examples of the substituent of “the hydrocarbon group” in “thehydrocarbon group which may be optionally substituted” include halogenatoms (e.g., fluorine, chlorine, bromine, iodine, etc.); a nitro group;a cyano group; a hydroxyl group; lower alkyl groups which may beoptionally halogenated (e.g., C₁₋₆ alkyl groups which may be optionallyhalogenated such as methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc.); lower alkoxy groups (e.g., C₁₋₆ alkoxygroups such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy,butoxy, isobutoxy, cyclobutoxy, pentyloxy, cyclopentyloxy, hexyloxy,cyclohexyloxy, etc.); an amino group; mono-lower alkylamino groups(e.g., mono-C₁₋₆ alkylamino groups such as methylamino, ethylamino,etc.); di-lower alkylamino groups (e.g., di-C₁₋₆ alkylamino groups suchas dimethylamino, diethylamino, etc.); a carboxyl group; lower alkylcarbonyl groups (e.g., C₁₋₆ alkylcarbonyl groups such as acetyl,propionyl, etc.); lower alkoxycarbonyl groups (e.g., C₁₋₆ alkoxycarbonylgroups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, etc.); a carbamoyl group; mono-lower alkylcarbamoylgroups (e.g., mono-C₁₋₆ alkylcarbamoyl groups such as methylcarbamoyl,ethylcarbamoyl, etc.); di-lower alkylcarbamoyl groups (e.g., di-C₁₋₆alkylcarbamoyl groups such as dimethylcarbamoyl, diethylcarbamoyl,etc.); arylcarbamoyl groups (e.g., C₆₋₁₀ arylcarbamoyl groups such asphenylcarbamoyl, naphthylcarbamoyl, etc.); aryl groups (e.g., C₆₋₁₀ arylgroups such as phenyl, naphthyl, etc.); aryloxy groups (e.g., C₆₋₁₀aryloxy group such as phenyloxy, naphthyloxy, etc.); and loweralkylcarbonylamino groups which may be optionally halogenated (e.g.,C₁₋₆ alkylcarbonylamino groups which may be optionally halogenated suchas acetylamino, trifluoroacetylamino, etc.)

[0032] “The hydrocarbon group” of “the hydrocarbon group which may beoptionally substituted” may have 1 to 5, preferably 1 to 3, substituentsdescribed above at places where the substitution is possible, and in thecase of the hydrocarbon group having 2 or more substituents, thesubstituents may be same or different.

[0033] Examples of the term “the heterocyclic group” in “a heterocyclicgroup which may be optionally substituted” of the present specificationinclude 5- to 14-membered, preferably 5- to 10-membered, (monocyclic totricyclic, preferably monocyclic to bicyclic) heterocyclic groups having1 to 4, preferably 1 to 3 atoms which are 1 or 2 kinds of hetero atomsselected from the group consisting of nitrogen, oxygen and sulfur atomsas well as carbon atoms. More specifically, examples of the heterocyclicgroup include 5-membered ring groups having 1 to 4 hetero atoms selectedfrom the group consisting of oxygen, sulfur and nitrogen atoms as wellas carbon atoms such as 2- or 3-thienyl, 3-furyl, 1-, 2-, or 3-pyrrolyl,1-, 2-, or 3-pyrrolidinyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or5-isoxazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 3-, 4-,or 5-pyrazolyl, 2-, 3-, or 4-pyrazolidinyl, 2-, 4-, or 5-imidazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, etc.; 6-memberedring groups having 1 to 4 hetero atoms selected from the groupconsisting of oxygen, sulfur and nitrogen atoms as well as carbon atomssuch as 2-, 3-, or 4-pyridinyl, N-oxide-2-, 3-, or 4-pyridinyl, 2-, 4-,or 5-pyrimidinyl, N-oxide-2-, 4-, or 5-pyrimidinyl, thiomorpholinyl,morpholinyl, piperidino, 2-, 3-, or 4-piperidyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3-or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl, etc.; andbicyclic or tricyclic condensed ring groups having 1 to 4 hetero atomsselected from the group consisting of oxygen, sulfur and nitrogen atomsas well as carbon atoms (preferably, groups which are formed by thecondensation of the 5 or 6-membered ring groups described above and 1 or2 of 5- or 6-membered rings having 1 to 4 hetero atoms selected from thegroup consisting of oxygen, sulfur and nitrogen atoms as well as carbonatoms) such as indolyl, benzofuryl, benzoxazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,indolizinyl, quinolizinyl, 1,8-naphthyridinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothiazinyl,phenoxazinyl, etc. The heterocyclic group is preferably a 5- to7-membered (preferably 5- or 6-membered) heterocyclic ring having 1 to 3hetero atoms selected from the group consisting of oxygen, sulfur andnitrogen atoms as well as carbon atoms.

[0034] Examples of the substituent of “the heterocyclic group” of “theheterocyclic group which may be optionally substituted” include halogenatoms (e.g., fluorine, chlorine, bromine, iodine, etc.); lower alkylgroups (e.g., C₁₋₆ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.);cycloalkyl groups (e.g., C₃₋₆ cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.); lower alkynyl groups (e.g.,C₂₋₆ alkynyl groups such as ethynyl, l-propynyl, propargyl, etc.); loweralkenyl groups (e.g., C₂₋₆ alkenyl groups such as vinyl, allyl,isopropenyl, butenyl, isobutenyl, etc.); aralkyl groups (e.g., C₇₋₁₁aralkyl groups such as benzyl, α-methylbenzyl, phenethyl, etc.); arylgroups (e.g., C₆₋₁₀ aryl groups such as phenyl, naphthyl, etc.,preferably phenyl group); lower alkoxy groups (e.g., C₁₋₆ alkoxy groupssuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, etc.) ; aryloxy groups (e.g., C₆₋₁₀ aryloxygroups such as phenoxy, etc.); lower alkanoyl groups (e.g., C₁₋₆alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl,etc.); arylcarbonyl (e.g., C₆₋₁₀ arylcarbonyl groups such as benzoylgroup, naphthoyl group, etc.); lower alkanoyloxy groups (e.g., C₁₋₆alkanoyloxy groups such as formyloxy, acetyloxy, propionyloxy,butyryloxy, isobutyryloxy, etc.); arylcarbonyloxy groups (e.g., C₆₋₁₀arylcarbonyloxy groups such as benzoyloxy, naphthoyloxy, etc.); acarboxyl group; lower alkoxycarbonyl groups (e.g., C₁₋₆ alkoxy-carbonylgroups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, etc.); aralkyloxycarbonyl groups (e.g., C₇₋₁₁aralkyloxycarbonyl groups such as benzyloxycarbonyl, etc.); a carbamoylgroup; mono-, di- or tri-halogeno-lower alkyl groups (e.g., mono-, di-,or tri-halogeno-C₁₋₄ alkyl groups such as chloromethyl, dichloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, etc.); an oxo group; an amidinogroup; an imino group; an amino group; mono-lower alkylamino groups(e.g., mono-C₁₋₄ alkylamino groups such as methylamino, ethylamino,propylamino, isopropylamino, butylamino, etc.); di-lower alkylaminogroups (e.g., di-C₁₋₄ alkylamino groups such as dimethylamino,diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.); 3-to 6-membered cyclic amino groups having 1 to 3 hetero atoms selectedfrom the group consisting of oxygen, sulfur, and nitrogen atoms as wellas carbon atoms and a nitrogen atom (e.g., 3- to 6-membered cyclic aminogroups such as aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl,pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidinyl,morpholinyl, dihydropyridinyl, pyridinyl, N-methylpiperazinyl,N-ethylpiperazinyl, etc.), alkylenedioxy groups (e.g., C₁₋₃alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.); ahydroxyl group; a nitro group; a cyano group; a mercapto group; a sulfogroup, a sulfino group, a phosphono group, a sulfamoyl group,monoalkylsulfamoyl groups (e.g., mono-C₁₋₆ alkylsulfamoyl groups such asN-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl,N-isopropylsulfamoyl, N-butylsulfamoyl, etc.); dialkylsulfamoyl groups(e.g., di-C₁₋₆ alkylsulfamoyl groups such as N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl,etc.); alkylthio groups (e.g., C₁₋₆ alkylthio groups such as methylthio,ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,tert-butylthio, etc.); arylthio groups (e.g., C₆₋₁₀ arylthio groups suchas phenylthio, naphthylthio, etc.); lower alkylsulfinyl groups (e.g.,C₁₋₆ alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl,propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.); arylsulfinylgroups (e.g., C₆₋₁₀ arylsulfinyl groups such as phenylsulfinyl,naphthylsulfinyl, etc.); lower alkylsulfonyl groups (e.g., C₁₋₆alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, etc.); andarylsulfonyl groups (e.g., C₆₋₁₀ arylsulfonyl groups such asphenylsulfonyl, naphthylsulfonyl, etc.).

[0035] The “heterocyclic group” of the “heterocyclic group which may beoptionally substituted” may have 1 to 5, preferably 1 to 3, substituentdescribed above at the positions of the heterocyclic ring where thesubstitution is possible, and in the case of the ring having 2 or moresubstituents, the substituents may be same or different.

[0036] An example of the term “the amino group which may be optionallysubstituted” of the present specification, is an amino group which mayhave 1 or 2 “hydrocarbon groups which may be optionally substituted”described above. Preferred examples of the substituent of the “aminogroup” include C₁₋₆ alkyl groups which may be optionally substituted,and C₆₋₁₀ aryl groups which may be optionally substituted. Thesubstituents which the “C₁₋₆ alkyl group” and the “C₆₋₁₀ aryl group” mayhave are similar to the substituents of the “hydrocarbon groups”described above.

[0037] Examples of the term “the cyclic amino group or the heterocyclicgroup”, in the phrase “R⁴ and R⁵ may bind each other to form an cyclicamino group or a heterocyclic group with the nitrogen atom boundthereto”, of the present specification include 3- to 6-membered cyclicamino groups having 1 to 3 hetero atoms selected from the groupconsisting of oxygen, sulfur, and nitrogen atoms as well as carbon atomsand a nitrogen atom (e.g., aziridinyl, azetidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl,morpholinyl, dihydropyridinyl, pyridinyl, N-methylpiperazinyl,N-ethylpiperazinyl, etc.).

[0038] Examples of the term “the thiol group which may be optionallysubstituted” of the present specification include thiol groups which mayhave the “hydrocarbon group which may be optionally substituted” assubstituents. Preferred examples of the substituent which the “thiolgroup” may have include C₁₋₆ alkyl groups which may be optionallysubstituted, C₆₋₁₀ aryl groups which may be optionally substituted, etc.Examples of the substituent which the “C₁₋₆ alkyl group” and the “C₆₋₁₀aryl group” may have are similar to the substituents of the “hydrocarbongroup” described above.

[0039] Examples of the term “lower alkyl group”, in the phrase “loweralkyl group which may be optionally substituted”, of the presentspecification include C₁₋₆ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the lower alkylgroup may have 1 to 3 substituents similar to those of the “hydrocarbongroup” described above.

[0040] Examples of the term “lower alkoxy group”, in the phrase “loweralkoxy group which may be optionally substituted”, of the presentspecification include C₁₋₆ alkoxy groups such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.and the lower alkoxy group may have 1 to 3 substituents similar to thoseof the “hydrocarbon group” described above.

[0041] Examples of the term “benzene ring which may be optionallysubstituted” of the present specification include benzene rings having,at the position where the substitution is possible, 1 to 3 (preferably 1or 2) same or different substituents selected from the group ofsubstituents consisting of halogen atoms (e.g., fluorine, chlorine,bromine, iodine, etc.); hydrocarbon groups which may be optionallysubstituted; amino groups which may be optionally substituted; amidegroups (e.g., C₁₋₆ acylamino groups such as acetamide, etc., preferablyC₁₋₆ alkanoylamino groups, etc.); lower alkoxy groups which may beoptionally substituted; lower alkylenedioxy groups (e.g., C₁₋₆alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.); andsubstituents similar to those which the “heterocyclic group” in“heterocycle group which may be optionally substituted” may have.

[0042] Examples of the term “hydrocarbon group which may be optionallysubstituted”, the “amino group which may be optionally substituted” andthe “lower alkoxy group which may be optionally substituted” are similarto those described above in detail. In the case of the “hydrocarbongroup”, the “amino group” and the “lower alkoxy group” having 2 or moresubstituents, the substituents may be same or different.

[0043] The “benzene ring which may be optionally substituted” ispreferably a benzene ring which is substituted by 1 to 3 substituentsselected, for example, from the group consisting of halogen atoms (e.g.,fluorine, chlorine, etc.), C₁₋₆ alkyl groups (e.g., methyl, ethyl,etc.), and mono-C₁₋₆ alkylamino groups.

[0044] The “carboxyl group which may be optionally esterified” of R¹, X,Y, Z, R^(1a), X^(a), X′, Y′, and Z′ in the compound (I) , (I′), (Ia) and(Ia′), is a group represented by —COOR⁴. Here, R⁴ is a hydrogen atom ora hydrocarbon group which may be optionally substituted. The “carboxylgroup which may be optionally amidated” of R¹, X, Y, Z, R^(1a), X^(a),X′, Y′ and Z′ is a group represented by —CONR⁴R⁵. Here, R⁴ and R⁵ are,respectively, a hydrogen atom, a hydrocarbon group which may beoptionally substituted, or may bind each other to form a cyclic aminogroup or a heterocyclic group with the nitrogen atom bound thereto.

[0045] The “acyl group which may be optionally substituted” of X, Y, Z,X^(a), X′, Y′ and Z′ is a group represented by COR⁶, SOR⁶ or SO₂R⁶ Here,R⁶ is the “hydrocarbon group which may be optionally substituted”, orthe “heterocycle group which may be optionally substituted”, both ofwhich are described above.

[0046] Preferably, the heterocyclic group of R³ is a nitrogen-containingaromatic heterocyclic group, especially, a 6-memberednitrogen-containing aromatic heterocycle group, for example, a pyridinering. The substituents thereof are those of the “heterocyclic groupwhich may be optionally substituted” described above, and R³ may be aquinoline ring which is formed by the condensation of thenitrogen-containing heterocyclic group and a benzene ring. Theunsaturated heterocyclic group of R³′ having only a nitrogen atom as thehetero atom is preferably an 6-membered unsaturated heterocyclic grouphaving only a nitrogen atom, for example, a pyridine ring. Thesubstituents thereof may be those of the “heterocyclic group which maybe optionally substituted” described above, and R³′ may be a quinolinering which is formed by the condensation of the nitrogen-containingheterocyclic group and a benzene ring.

[0047] X and X′ are, respectively, preferably a hydrogen atom, an oxygenatom, OR⁴ (R⁴ is a hydrogen atom or a hydrocarbon group which may beoptionally substituted), or a hydrocarbon group which may be optionallysubstituted.

[0048] Y and Y′ are, respectively, preferably a hydrogen atom, ahydrocarbon group which may be optionally substituted, COR⁴ or COOR⁴,more preferably COR⁴ or COOR⁴. Z is preferably a hydrogen atom, anoxygen atom, OR⁴ or a hydrocarbon group which may be optionallysubstituted (herein, R⁴ is a hydrogen atom or a hydrocarbon group whichmay be optionally substituted).

[0049] Examples of the homocyclic ring of the “5- to 7-memberedhomocyclic or heterocyclic ring which may be optionally substituted”represented by ring A or ring B include cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclopentadiene, cyclohexene,cyclohexadiene, benzene, cycloheptene, cycloheptadiene, etc., preferablybenzene, cyclopentane, cyclohexane, cycloheptane, and most preferablybenzene.

[0050] Examples of the heterocyclic ring of the “5- to 7-memberedhomocyclic or heterocyclic ring which may be optionally substituted”represented by ring A or ring B include aromatic heterocyclic rings suchas furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, oxadiazole, furazan, thiadiazole, triazole,pyridine, pyridazine, pyrimidine, pyrazine, triazine; non-aromaticheterocyclic rings (aliphatic heterocycles) such as azetidine, oxetane,pyrrolidine, piperidine, tetrahydropyran, morpholine, thiomorpholine,piperazine; and non-aromatic heterocyclic rings wherein part or all ofthe double bonds in aromatic heterocyclic rings are saturated; etc.

[0051] The substituents of the “5- to 7-membered homocyclic orheterocyclic ring which may be optionally substituted” are those whichthe “heterocyclic ring which may be optionally substituted” describedabove may have, and the number of substitution is also same as that ofthe heterocyclic ring.

[0052] n is preferably 0.

[0053] Preferred specific examples of the compound (I) and (I′) of thepresent invention include4-hydroxy-3-methyl-1-(2-pyridinyl)-pyrazolo[3,4-b]pyridine-5-carboxylicacid or an ester thereof, especially, ethylester.

[0054] The heterocyclic group of R^(3a) is preferably an unsaturatedheterocyclic group having 2 or less nitrogen atoms as the hetero atoms,or an unsaturated monocyclic heterocyclic group having a nitrogen atomand a sulfur atom as the hetero atoms, more preferably anitrogen-containing aromatic heterocyclic group, especially, anitrogen-containing 6-membered aromatic heterocyclic group, for example,a pyridine ring. Substituents thereof may be those of the “heterocyclicgroup which may be optionally substituted” described above, and R^(3a)may be a quinoline ring which is formed by the condensation of thenitrogen-containing heterocyclic group and a benzene ring. Examples ofthe unsaturated heterocyclic groups of R^(3ab) having 2 or less nitrogenatoms as the hetero atoms or the unsaturated monocyclic heterocyclicgroups having a nitrogen atom and a sulfur atom as the hetero atomsinclude preferably nitrogen-containing aromatic heterocyclic groups,especially, 6-membered nitrogen-containing aromatic heterocyclic groups,for example, a pyridine ring. The substituents thereof may be those ofthe “heterocyclic group which may be optionally substituted” describedabove, and R^(3ab) may be a quinoline ring which is formed by thecondensation of the nitrogen-containing heterocyclic and a benzene ring.

[0055] Further, X^(a) is preferably an oxygen atom or OR^(4a) (R^(4a) isa hydrogen atom or a hydrocarbon group which may be optionallysubstituted), and ring B^(a) is preferably a benzene ring which may beoptionally substituted. Especially, a compound (Ia) or (Ia′) having anitrogen-containing aromatic heterocyclic group which may be optionallysubstituted as R^(3a) or R^(3ab) and a benzene ring which may beoptionally substituted as ring B^(a) is favorable.

[0056] m is preferably 0.

[0057] Especially preferred examples of the compound (Ia) or (Ia′)include6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,3-methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,6-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,7-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,3-ethyl-6,7-difluoro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,6,7-difluoro-3-methyl-1-(3-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,6,7-difluoro-3-methyl-1-(6-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,6,7-difluoro-3-methyl-1-(6-phenyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,5-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,and 1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one.

[0058] As the salts of the compound (I), (I′), (Ia) and (Ia′) of thepresent invention, for example, pharmaceutically acceptable salts areused. Examples of the salt include salts with inorganic bases, withorganic bases, with inorganic acids, with organic acids, with basic oracidic amino acids, etc. Suitable examples of the salt with an inorganicbase include alkali metal salts such as sodium salt, potassium salt,etc., alkali-earth metal salts such as calcium salt, magnesium salt,etc., and aluminum salt, ammonium salt, etc. Preferred examples of thesalt with an organic base include salts with trimethylamine,triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine,diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine,N,N-dibenzylethylene diamine, etc. Preferred examples of the salt withan inorganic acid include salts with hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, etc. Preferredexamples of the salt with an organic acid include salts such as formate,acetate, trifluoroacetate, phthalate, fumarate, oxalate, tartrate,maleate, citrate, succinate, malate, methanesulfonate, benzenesulfonate,p-toluenesulfonate, etc. Preferred examples of the salt with a basicamino acid include salts with arginine, lysine, ornithine, etc., andexamples of the salt with an acidic amino acid include salts withaspartic acid, glutamic acid, etc.

[0059] The salt is preferably a pharmaceutically acceptable salt, and inthe case of the compound (I), (I′), (Ia) or (Ia′) having a basicfunctional group, preferred examples of the salt include salts withinorganic acids such as hydrochloride, hydrobromide, nitrate, sulfate,phosphate, etc., and salts with organic acids such as acetate,phthalate, fumarate, tartrate, maleate, citrate, succinate,methanesulfonate, p-toluenesulfonate, etc., and in the case of thecompound (I), (I′), (Ia) or (Ia′) having an acidic functional group,examples of the salt include alkali metal salts such as sodium salt,potassium salt, etc., alkali-earth metal salts such as calcium salt,magnesium salt, etc., ammonium salt, etc.

[0060] Compounds (I) and (I′) or the salts thereof of the presentinvention may be produced according to a similar method, and therefore,a process for producing a compound (I′) having unsubstituted as R² willbe described below as an example of the process.

[0061] The compound (I′) of the present invention can be prepared, forexample, according to a method represented by the reaction formula 1 ora modified method thereof.

[0062] Each of the compounds (II) to (IV) in the reaction formula may bepresent as a salt, and in such a case, a salt is similar to the salts ofthe compounds (I) and (I′) is used.

[0063] Each of the symbols in reaction formula 1 has the same meaning asdescribed above.

[0064] The compound (II) can be prepared according to methods known inthe art, for example, the methods described in Shin Jikken Kagaku Koza,vol.14, p.1573-1585, Jikken Kagaku Koza (4th Ed.), vol.20, p.338-342,(Chem. Soc. Japan, Ed.), J. Med. Chem., vol.28, p.1394 (1985), Eur. J.Med. Chem., vol.24, p.435 (1989), J. Amer. Chem. Soc., vol.81, p.2456(1959), Japanese Patent Laid-open Publication No.H02 (1990)-229168,Japanese Patent Laid-open Publication No.H02 (1990)-229169, JapanesePatent Publication No.S56 (1981)-37231, U.S. Pat. No. 4,260,767, Can. J.Chem., vol.48, p.3554 (1970), J. Chem. Soc., p.3830 (1959), and YakugakuZasshi, vol.73, p.598 (1953), with or without slight modifications.

[0065] The compound (III) can be prepared according to methods known inthe art, for example, the methods described in U.S. Pat. No. 3,414,580,U.S. Pat. No. 3,755,340, EP389189, Japanese Patent Publication No.S56(1981)-37231 (1981), U.S. Pat. No. 4,260,767 (1981), Eur. J. Med. Chem.,vol.24, p.435 (1989), J. Amer. Chem. Soc., vol.81, p.2456, 2460 (1959),and Synthesis, p.337 (1997), with or without slight modifications.

[0066] The compound (IV) can be prepared from the compound (III) and aβ-ketoester derivative. Substituted β-ketoester derivative can beprepared according to methods known in the art, for example, the methodsdescribed in U.S. Pat. No. 4,804,760, U.S. Pat. No. 4,994,610, Org.Synth., vol.28, p.60 (1948), and Org. Synth. Coll. IV, p.285 (1963),with or without slight modifications. The β-ketoester derivative is usedin an amount of about 0.8 to 10.0 moles, preferably about 1.0 to 3.0moles per mole of the compound (III). The reaction may be favorablycarried out in the absence of a solvent, or in a solution using asolvent which does not interfere with the reaction. Preferred examplesof the solvent include, but not limited to so far as the reaction canproceed, ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., nitritessuch as acetonitrile, propionitrile, etc., sulfoxides such asdimethylsulfoxide, etc., or a mixture thereof. The reaction period mayvary according to the reagents used and the solvent, but is usually 10minutes to 12 hours, preferably 20 minutes to 8 hours. The reactiontemperature is usually 0 to 200° C., preferably 0 to 150° C.

[0067] The compound (I′; X═OH) can be prepared by subjecting thecompound (IV) to a cyclization reaction known in the art. Thecyclization reaction may be carried out according to methods, forexample, by heating, by the use of an acidic compound, or the modifiedmethod thereof.

[0068] The cyclization by heating is favorably carried out in theabsence of a solvent, or in a solution using a solvent inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, high-boiling point hydrocarbons suchas 1,2,3,4-tetrahydronaphthalene, etc., and high-boiling point etherssuch as diphenylether, diethyleneglycol dimethylether, etc., or amixture thereof. The reaction period is usually 5 minutes to 24 hours,preferably 10 minutes to 6 hours. The reaction temperature is usually 80to 300° C., preferably 100 to 250° C.

[0069] In the case of the cyclization being carried out by using anacidic compound, an acidic compound, e.g., methanesulfonic acid,phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride,phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuricacid, polyphosphoric acid, p-toluenesulfonic acid, etc., or a mixturethereof, is used. The acidic compound is used in an amount of about 0.5to 100 moles, preferably about 1.0 to 20 moles per mole of the compound(IV). The reaction may be favorably carried out in the absence of asolvent or in a solution using a solvent which is inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, aromatic hydrocarbons such asbenzene, toluene, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., acid anhydrides such as acetic anhydride, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixed solvent thereof. Thereaction period is usually 5 minutes to 12 hours, preferably 10 minutesto 6 hours. The reaction temperature is usually 0 to 250° C., preferably0 to 200° C. The product of the cyclization reaction (I′; X═OH) may beused in the following reaction as it is in the reaction mixture or as acrude product, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0070] The compound (I′; X═OH) can be prepared by subjecting thecompound (III) to a cyclization reaction with a β-ketoester derivativeknown in the art, for example, the methods described in Japanese PatentLaid-open Publication No.H06 (1994)-199855, Japanese Patent Laid-openPublication No.S58 (1983)-67685, and Angew. Chem., Int. Ed. Engl., p.958(1967), with or without slight modifications. The cyclization reactionmay be carried out according to methods, for example, by heating and bythe use of an acidic compound, or the modified method thereof. Thecyclization by heating is favorably carried out in a solution using asolvent inactive to the reaction. Preferred examples of the solventinclude, but not limited to so far as the reaction can proceed,high-boiling point hydrocarbons such as 1,2,3,4-tetrahydronaphthalene,etc., and high-boiling point ethers such as diphenylether,diethyleneglycol dimethylether, etc., or a mixture thereof. The reactionperiod is usually 5 minutes to 24 hours, preferably 10 minutes to 6hours. The reaction temperature is usually 50 to 300° C., preferably 100to 250° C. In the case of the cyclization being carried out by using anacidic compound, an acidic compound, e.g., methanesulfonic acid,phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride,phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuricacid, polyphosphoric acid, p-toluenesulfonic acid, trifluoroaceticanhydride, trifluoroacetic acid, acetic acid, acetic anhydride, etc., ora mixture thereof is used. The acidic compound is used in an amount ofabout 0.5 to 100 moles, preferably about 1.0 to 20 moles per mole of thecompound (III). The reaction may be favorably carried out in the absenceof a solvent or in a solution using a solvent which is inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, aromatic hydrocarbons such asbenzene, toluene, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., acid anhydrides such as acetic anhydride, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixed solvent thereof. Theβ-ketoester derivative is used in an amount of about 0.8 to 10 moles,preferably about 1.0 to 3.0 moles per mole of compound (III). Thereaction period may vary according to the reagents used and the solvent,but is usually about 5 minutes to 24 hours, preferably 10 minutes to 12hours. The reaction temperature is usually 0 to 300° C., preferably 50to 200° C. The product of the cyclization reaction (I′; X═OH) may beused in the following reaction as it is in the reaction mixture or as acrude product, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0071] The compound (I′; Z═OH) may be prepared by subjecting thecompound (III) to a cyclization reaction with a β-ketoester derivative,known in the art, for example, the methods described in J. Heterocycl.Chem., vol.12, p.517 (1975), and J. Chem. Soc., Perkin Trans. 1, p.938(1980), with or without slight modification. The cyclization reactionmay be carried out according to methods, for example, by the use of anacidic compound, or the modified method thereof. Examples of the acidiccompound include acidic compounds such as methanesulfonic acid,phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride,phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuricacid, polyphosphoric acid, p-toluenesulfonic acid, trifluoroaceticanhydride, trifluoroacetic acid, acetic acid, acetic anhydride, or amixture thereof. The acidic compound is used in an amount of about 0.5to 100 moles, preferably about 1.0 to 20 moles per mole of the compound(III). The reaction may be favorably carried out in the absence of asolvent or in a solution using a solvent which is inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, aromatic hydrocarbons such asbenzene, toluene, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., acid anhydrides such as acetic anhydride, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixed solvent thereof. Theβ-ketoester derivative is used in an amount of about 0.8 to 10 moles,preferably about 1.0 to 3.0 moles per mole of the compound (III). Thereaction period may vary according to the reagents used and the solvent,but is usually about 1 minute to 120 hours, preferably 5 minutes to 60hours. The reaction temperature is usually 0 to 300° C., preferably 50to 200° C. The product of the cyclization reaction (I′; Z═OH) may beused in the following reaction as it is in the reaction mixture or as acrude product, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0072] The compound (I′; X═Cl) can be prepared by subjecting thecompound (I′; X═OH) to a halogenation reaction in the presence of anacidic compound known in the art. The acidic compounds include, forexample, phosphorus oxychloride, phosphorus pentachloride, phosphorustrichloride, thionyl chloride, etc. The acidic compound is used in anamount of about 0.2 to 100 moles, preferably about 0.3 to 30 moles permole of compound (I′; X═OH). The reaction may be favorably carried outin the absence of a solvent or in a solution using a solvent which isinactive to the reaction. Preferred examples of the solvent include, isbut not limited to so far as the reaction can proceed, aromatichydrocarbons such as benzene, toluene, etc., saturated hydrocarbons suchas cyclohexane, hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixturethereof. The reaction period is usually 10 minutes to 12 hours,preferably 30 minutes to 6 hours. The reaction temperature is usually 0to 200° C., preferably 0 to 150° C. The product (I′; X═Cl) may be usedin the following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0073] The compound (I′; X=alkoxy) can be prepared by a reaction of thecompound (I′; X═OH) and a corresponding alkylating agent (e.g.,substituted alkyl halides, substituted alcohol sulfonic esters, etc.) inthe presence of a base. The alkylating agent is used in an amount ofabout 0.8 to 50 moles, preferably about 1.0 to 10 moles per mole of thecompound (I′; X═OH). Examples of the base include inorganic bases suchas sodium carbonate, potassium carbonate, sodium bicarbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., and metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium tert-butoxide, etc. The base isused in an amount of about 0.8 to 10 moles, preferably about 1.0 to 3.0moles per mole of the compound (I′; X═OH). The reaction may be favorablycarried out in a solution using a solvent which is inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, ethers such as diethylethertetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbons suchas benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., nitrites such as acetonitrile, propionitrile,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof. The reaction period is usually 30 minutes to 24 hours,preferably 1 to 12 hours. The reaction temperature is usually −20 to200° C., preferably 0 to 150° C. The product (I′:X=alkoxy) may be usedin the following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0074] The compound (I′; X=alkoxy) can also be prepared in a reaction ofthe compound (I′; X═Cl) and a corresponding substituted alcohol in thepresence of a base. Examples of the base include inorganic bases such assodium carbonate, potassium carbonate, sodium bicarbonate, etc., alkalimetal hydrides such as sodium hydride, potassium hydride, etc., metalamides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., and metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium tert-butoxide, etc. The base isused in an amount of about 0.8 to 5.0 moles, preferably about 1.0 to 3.0moles per mole of the compound (I′; X═Cl). The reaction may be favorablycarried out in a solution using a solvent which is inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, ethers such as diethylether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbons suchas benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., and sulfoxides such as dimethylsulfoxide,etc., or a mixed solvent thereof. The reaction period is usually 10minutes to 48 hours, preferably 15 minutes to 12 hours. The reactiontemperature is usually 0 to 200° C., preferably 40 to 120° C. Theproduct (I′; X=alkoxy) may be used in the following reaction as it is inthe reaction mixture or as a crude product, but also isolated from thereaction mixture by the common methods, and can be easily purified byseparation means such as recrystallization, distillation,chromatography, etc.

[0075] The compound (I′; X═NH₂) can be prepared in a reaction of thecompound (I′; X═Cl) and sodium azide and subsequent catalytic reductionof the resulting azide. Sodium azide is used in an amount of about 0.8to 10 moles, preferably about 1.0 to 3.0 moles per mole of the compound(I′; X═Cl). The reaction may be favorably carried out in a solutionusing a solvent which is inactive to the reaction. Preferred examples ofthe solvent include, but not limited to so far as the reaction canproceed, ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., pyridine, hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,and sulfoxides such as dimethylsulfoxide, etc., or a mixture thereof.The reaction period is usually 5 minutes to 12 hours, preferably 10minutes to 3 hours. The reaction temperature is usually 0 to 200° C.,preferably 20 to 150° C. The azide product thus obtained may be used inthe following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0076] Subsequently, by subjecting the azide thus obtained to acatalytic reduction reaction under hydrogen atmosphere in the presenceof a variety of catalysts, the compound (I′; X═NH₂) can be prepared.Examples of the catalyst used include platinum oxide, platinum onactivated carbon, palladium on activated carbon, palladium on bariumsulfate, nickel, copper-chromium oxide, rhodium, cobalt, ruthenium, etc.The catalyst is used in an amount of about 1.0 to 1000% by weight,preferably about 5.0 to 300% by weight per the azide. The reaction maybe favorably carried out in a solution using a solvent which is inactiveto the reaction. Preferred examples of the solvent include, but notlimited to so far as the reaction can proceed, alcohols such asmethanol, ethanol, propanol, etc., ethers such as diethylether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., saturatedhydrocarbons such as cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., organic acids suchas formic acid, acetic acid, etc., and water, or a mixture thereof. Thereaction period may vary according to the activity and the quantity ofthe catalyst used, but is usually 15 minutes to 24 hours, preferably 30minutes to 6 hours. The reaction temperature is usually 0 to 120° C.,preferably 20 to 80° C. The reaction pressure is usually 1 to 100 atm.An additive (an accelerator) may be added into the reaction system toincrease the activity of the catalyst. Preferred examples of the acidicadditive include inorganic acids such as hydrochloric acid, sulfuricacid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid,etc., and organic acids such as acetic acid, trifluoroacetic acid,oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid,succinic acid, methanesulfonic acid, p-toluenesulfonic acid,10-camphorsulfonic acid, etc. Preferred examples of the basic additiveinclude sodium hydroxide, potassium hydroxide, etc. The product (I′;X═NH₂) may be used in the following reaction as it is in the reactionmixture or as a crude product, but also isolated from the reactionmixture by the common methods, and can be easily purified by separationmeans such as recrystallization, distillation, chromatography, etc.

[0077] The compound (I′; X=alkylamine) can be prepared in a reaction ofthe compound (I′; X═Cl) and an alkyl amine, in the presence of a base ifdesired. The alkyl amine is used in an amount of about 0.1 to 1000moles, preferably about 1.0 to 200 moles per mole of the compound (I′;X═Cl). Example of the base include inorganic bases such as sodiumcarbonate, potassium carbonate, sodium bicarbonate, etc., aromaticamines such as pyridine, lutidine, etc., and tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc. The base is used in anamount of about 0.1 to 50 moles, preferably about 1.0 to 10 moles permole of the compound (I′; X═Cl). The reaction may be favorably carriedout in a solution using a solvent which is inactive to the reaction.Preferred examples of the solvent include, but not limited to so far asthe reaction can proceed, alcohols such as methanol, ethanol, propanol,etc., hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N′N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc., nitrites such as acetonitrile,propionitrile, etc., water, etc., or a mixture thereof. The reactionperiod may vary according to the reagents used and the solvent, but isusually 10 minutes to 48 hours, preferably 30 minutes to 20 hours. Thereaction temperature is usually 0 to 250° C., preferably 20 to 150° C.In the case where a reaction reagent has a low boiling point, thesubstitution reaction can be carried out in a similar condition byheating and stirring the reaction mixture under pressure, for example inan autoclave. The product (I′: X=alkylamine) may be used in thefollowing reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0078] The compound (I′; Y═COOH) can be prepared in a hydrolysisreaction known in the art of the compound (I′; Y=ester) in the presenceof an acid or a base. For the acid-catalyzed hydrolysis, mineral acidssuch as hydrochloric acid, sulfuric acid, etc., Lewis acids such asboron trichloride, boron tribromide, etc., a mixture of a Lewis acid anda thiol or a sulfide, and organic acids such as trifluoroacetic acid,p-toluenesulfonic acid, etc., are commonly used as the catalyst. For thebase-catalyzed hydrolysis, metal hydroxides such as sodium hydroxide,potassium hydroxide, barium hydroxide, etc., metal carbonates such assodium carbonate, potassium carbonate, etc., metal alkoxides such assodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., andorganic bases such as triethylamine, imidazole, formamidine, etc., arecommonly used as the catalyst. The acid and the base are used,respectively, in an amount of about 0.1 to 100 moles, preferably about0.5 to 10 moles per mole of the compound (I′). The reaction may befavorably carried out in the absence of a solvent or in a solution usinga solvent which is inactive to the reaction. Preferred examples of thesolvent include, but not limited to so far as the reaction can proceed,alcohols such as methanol, ethanol, propanol, etc., aromatichydrocarbons such as benzene, toluene, etc., saturated hydrocarbons suchas cyclohexane, hexane, etc., organic acids such as formic acid, aceticacid, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., ketones suchas acetone, methylethylketone, etc., sulfoxides such asdimethylsulfoxide, etc., and water, etc., or a mixed solvent thereof.The reaction period is usually 5 minutes to 24 hours, preferably 10minutes to 12 hours. The reaction temperature is usually −10 to 200° C.,preferably 0 to 150° C. The product (I′; Y═COOH) may be used in thefollowing reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0079] The compound (I′; Y═H) can be prepared by subjecting the compound(I′; Y═COOH, ester) to a decarboxylation reaction known in the art. Thereaction can be carried out, according to methods, for example, byheating and by the use of an acidic compound, or the modified methodsthereof. In the case where the cyclization is conducted by heating, thereaction may be favorably carried out in the absence of a solvent or ina solution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, high-boiling point hydrocarbons such as1,2,3,4-tetrahydronaphthalene, etc., high-boiling point ethers such asdiphenylether, diethyleneglycol dimethylether, etc., anilines such asN,N-dimethylaniline, N-methylaniline, etc., and nitrogen-containingaromatic compounds such as pyridine, quinoline, etc., or a mixturethereof. The reaction period is usually 5 minutes to 12 hours,preferably 10 minutes to 10 hours. The reaction temperature is usually100 to 300° C., preferably 100 to 250° C. In the case where an acidiccompound is used for cyclization, an acidic compound, e.g.,methanesulfonic acid, phosphorus pentoxide, phosphorus oxychloride,phosphorus pentachloride, phosphorus trichloride, thionyl chloride,hydrochloric acid, sulfuric acid, polyphosphoric acid, p-toluenesulfonicacid, etc, or a mixture thereof is commonly used. The acidic compound isused in an amount of about 0.5 to 100 moles, preferably about 1.0 to 20moles per mole of the compound (I′; Y═COOH, ester). The reaction may befavorably carried out in the absence of a solvent or in a solution usinga solvent which is inactive to the reaction. Preferred examples of thesolvent include, but not limited to so far as the reaction can proceed,aromatic hydrocarbons such as benzene, toluene, etc., saturatedhydrocarbons such as cyclohexane, hexane, etc., ethers such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., acid anhydrides such as acetic anhydride,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof. The reaction period is usually 5 minute to 12 hours, preferably10 minutes to 6 hours. The reaction temperature is usually 0 to 250° C.,preferably 10 to 200° C. The product of the cyclization reaction (I′;Y═H) may be used in the following reaction as it is in the reactionmixture or as a crude product, but also isolated from the reactionmixture by the common methods, and can be easily purified by separationmeans such as recrystallization, distillation, chromatography, etc.

[0080] The compound (I′; Y═CO-alkyl, CO-aryl) can be prepared in areaction of the compound (I′; Y=reactive derivative of carboxylic acid)with an alkylating or an arylating agent known in the art (e.g.,Grignard reagents, organolithium reagents, organocerium reagents,organotitanium reagents, organozinc reagents, organoaluminum reagents,and organocopper reagents). Examples of the reactive derivative of thecarboxylic acid include acid halides (e.g., acid chlorides, acidbromides, etc.); acid amides (e.g., acid amides with pyrazole,imidazole, benzotriazole, etc.); mixed acid anhydrides [e.g., mono C₁₋₄alkylcarbonate mixed acid anhydrides such as monomethylcarbonate,monoethylcarbonate, monoisopropylcarbonate, mono-tert-butylcarbonate;mono-C₇₋₁₀ aralkylcarbonate mixed acid anhydrides such asmonobenzylcarbonate, mono(p-nitrobenzyl)carbonate, monoallylcarbonate;C₁₋₆ aliphatic carboxylate mixed acid anhydrides such as acetate,cyanoacetate, propionate, butyrate, isobutyrate, valerate, isovalerate,pivalate, trifluoroacetate, trichloroacetate, acetoacetate; C₇₋₁₁aromatic carboxylate mixed acid anhydrides such as benzoate, p-toluate,p-chlorobenzoate; organic sulfonate mixed acid anhydrides such asmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,etc.)]; acid azides; activated esters (e.g., diethoxyphosphoric ester,diphenoxyphosphoric ester, p-nitrophenylester, 2,4-dinitrophenylester,cyanomethylester, pentachlorophenylester, ester with N-hydroxysuccimide,ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole,ester with 6-chloro-1-hydroxybenzotriazole, ester with1-hydroxy-1H-2-pyridone, etc.); and activated thioesters (e.g.,2-pyridylthioester, 2-benzothiazolylthioester, etc.); etc. Thealkylating agent or the arylating agent is used in an amount of about0.8 to 20 moles, preferably about 1.0 to 5.0 moles per mole of thecompound (I′; Y=reactive derivative of carboxylic acid). Preferredexamples of the solvent to be used for dilution include, but not limitedto so far as the reaction can proceed, aromatic hydrocarbons such asbenzene, toluene, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., halogenated hydrocarbons such as chlorotoluene, etc., andethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., or a mixture thereof. The reaction period isusually 10 minutes to 20 hours, preferably 15 minutes to 6 hours. Thereaction temperature is usually −78 to 200° C., preferably −78 to 100°C. In the case where an acid halide is used as the reactive derivativeof the carboxylic acid, the reaction may be carried out in the presenceof a deacidifying agent to be used for the purpose of removing hydrogenhalide released in the reaction system. Examples of the deacidifyingagent include inorganic bases such as sodium carbonate, potassiumcarbonate, sodium bicarbonate, etc., aromatic amines such as pyridine,lutidine, etc., and tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc.

[0081] Instead of using the reactive derivative, the carboxylic acid orthe salt thereof may be directly reacted with an alkylating agent or anarylating agent in the presence of a proper condensing agent. Examplesof the condensing agent include N,N-disubstituted carbodiimides such asN,N-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, etc.,azolides such as N,N-carbonyldiimidazole, etc., dehydrating agents suchas N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorusoxychloride, alkoxyacetylene, etc., and 2-halogenopyridinium salts suchas 2-chloromethylpyridinium iodide, 2-fluoro-1-methylpyridinium iodide,etc. When the condensing agent is used, the reaction seems to proceedvia a reactive derivative of carboxylic acid. The condensing agent isused in an amount of about 0.8 to 5.0 moles, preferably about 1.0 to 2.0moles per mole of compound (I′; Y=carboxylic acid). The reaction may befavorably carried out in a solution using a solvent which is inactive tothe reaction. Preferred examples of the solvent include, but not limitedto so far as the reaction can proceed, ethers such as diethylether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbons suchas benzene, toluene, cyclohexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixturethereof. The reaction period may vary according to the reagents and thesolvent used, but is usually 10 minute to 24 hours, preferably 30minutes to 4 hours. The reaction temperature is usually −78 to 100° C.,preferably −78 to 70° C. The product (I′; Y═CO-alkyl, CO-aryl) may beused in the following reaction as it is in the reaction mixture or as acrude product, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0082] The compound (I′; Y=carboxamide) can be prepared by condensingthe compound (I′; Y=ester) and an amine derivative. The amine derivativeis used in an amount of about 0.8 to 100 moles, preferably about 1.0 to50 moles per mole of the compound (I′; Y=ester). The reaction may befavorably carried out in the absence of a solvent or in a solution usinga solvent which is inactive to the reaction. Preferred examples of thesolvent include, but not limited to so far as the reaction can proceed,ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,xylene, decalin, cyclohexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixturethereof. The reaction period may vary according to the reagents used andthe solvent, but is usually 5 minutes to 48 hours, preferably 10 minutesto 24 hours. The reaction temperature is usually 0 to 300° C.,preferably 20 to 250° C. In the case where a reaction reagent has a lowboiling point, the substitution reaction can be carried out in a similarcondition by heating and stirring the reaction mixture under pressure,for example in an autoclave. The product (I′; Y=carboxamide) may be usedin the following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0083] The compound (I′; Y=carboxamide) can also be prepared bycondensing the compound (I′; Y=reactive derivative of carboxylic acid)and an amine derivative. Examples of the reactive derivative ofcarboxylic acid include acid halides (e.g., acid chlorides, acidbromides, etc.); acid amides (e.g., acid amides with pyrazole,imidazole, benzotriazole, etc.); mixed acid anhydrides [e.g., mono C₁₋₄alkylcarbonate-mixed acid anhydrides such as monomethylcarbonate,monoethylcarbonate, monoisopropylcarbonate, mono-tert-butylcarbonate;mono-C₇₋₁₀-aralkylcarbonate mixed acid anhydrides such asmonobenzylcarbonate, mono (p-nitrobenzyl) carbonate, monoallylcarbonate;C₁₋₆ aliphatic carboxylate mixed acid anhydrides such as acetate,cyanoacetate, propionate, butyrate, isobutyrate, valerate, isovalerate,pivalate, trifluoroacetate, trichloroacetate, acetoacetate; C₇₋₁₁aromatic carboxylate mixed acid anhydrides such as benzoate, p-toluate,p-chlorobenzoate; organic sulfonate mixed acid anhydrides such asmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,etc.]; acid azides; activated esters (e.g., diethoxyphosphoric ester,diphenoxyphosphoric ester, p-nitrophenylester, 2,4-dinitrophenylester,cyanomethylester, pentachlorophenylester, ester with N-hydroxysuccimide,ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole,ester with 6-chloro-1-hydroxybenzotriazole, ester with1-hydroxy-1H-2-pyridone, etc.); and activated thioesters (e.g.,2-pyridylthioester, 2-benzothiazolylthioester, etc.). The aminederivative is used in an amount of about 0.8 to 10 moles, preferablyabout 1.0 to 5.0 moles per mole of compound (I′; Y=reactive derivativeof carboxylic acid). The reaction may be favorably carried out in asolution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, ethers such as diethylether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixture thereof. In the case wherean acid halide is used as the reactive derivative of the carboxylicacid, the reaction may be carried out in the presence of a deacidifyingagent to be used for the purpose of removing hydrogen halide releasedfrom the reaction system. Examples of the deacidifying agent includeinorganic bases such as sodium carbonate, potassium carbonate, sodiumbicarbonate, etc., aromatic amines such as pyridine, lutidine, etc., andtertiary amines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc. Thereaction period may vary according to the reagents used and the solvent,but is usually 10 minutes to 24 hours, preferably 30 minutes to 6 hours.The reaction temperature is usually 0 to 200° C., preferably 20 to 120°C.

[0084] Instead of using the reactive derivative, the carboxylic acid orthe salt thereof may be reacted directly with an amine derivative in thepresence of a proper condensing agent. Examples of the condensing agentinclude N,N-disubstituted carbodiimides such asN,N-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, etc.,azolides such as N,N-carbonyldiimidazole, etc., dehydrating agents suchas N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorusoxychloride, alkoxyacetylenes, etc., and 2-halogenopyridinium salts suchas 2-chloromethylpyridinium iodide, 2-fluoro-1-methylpyridinium iodide,etc. When the condensing agent is used, the reaction seems to proceedvia a reactive derivative of carboxylic acid. The condensing agent isused in an amount of about 0.8 to 5.0 moles, preferably about 1.0 to 2.0moles per mole of compound (I′; Y=carboxylic acid). The reaction may befavorably carried out in a solution using a solvent which is inactive tothe reaction. Preferred examples of the solvent include, but not limitedto so far as the reaction can proceed, ethers such as diethylether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbons suchas benzene, toluene, cyclohexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., nitrites such as acetonitrile, propionitrile,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixturethereof. The reaction period may vary according to the reagents used andthe solvent, but is usually 10 minutes to 24 hours, preferably 30minutes to 4 hours. The reaction temperature is usually −78 to 100° C.,preferably 0 to 70° C. The product (I′; Y=carboxamide) may be used inthe following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0085] The compounds (Ia) and (Ia′) of the present invention or thesalts thereof can also be prepared according to the method similar tothose described above, and hereinafter, a process for producing acompound represented by the formula (Ia) will be described as anexample. The compound (Ia) of the present invention can be prepared, forexample, according to methods represented by reaction formulas 2 and 3,or the modified method thereof.

[0086] Each of the compounds, (IIa), (IIIa), (V) to (X), in the reactionformulas may be present as a salt, and in such a case, a salt similar tothe salts of the compounds (Ia) is used.

[0087] Each of the symbols in the reaction formulas 2 and 3 has the samemeaning as described above.

[0088] The compound (V) in the reaction formula 2 can be preparedaccording to methods known in the art, for example, the methodsdescribed in J. Amer. Chem. Soc., vol.106, p.7195 (1984), ibid., vol.99,p.3734 (1976), ibid., vol.94, p.498 (1972), J. Chem. Soc. Perkin Trans.2, p.291 (1994), J. Heterocyclic. Chem. vol.27, p.2151 (1990), and J.Med. Chem., vol.26, p.420 (1983), with or without slight modifications.

[0089] The compound (VI) having a methyl group as R^(1a) can be preparedfrom the compound (V) and diketene according to methods known in theart, for example, the method described in J. Med. Chem., vol.38, p.1330(1995), with or without slight modifications. Diketene is used in anamount of about 1.0 to 20.0 moles, preferably about 1.0 to 10.0 molesper mole of the compound (V).

[0090] The reaction may be favorably carried out in a solution using asolvent which is inactive to the reaction. Preferred examples of thesolvent include, but not limited to so far as the reaction can proceed,ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixture thereof. The reactionperiod may vary according to the reagents used and the solvent, but isusually 30 minutes to 72 hours, preferably 30 minutes to 16 hours. Thereaction temperature is usually 0 to 100° C., preferably 0 to 70° C.

[0091] The compounds (VI) except the compound (VI) having a methyl groupas R^(1a) can be prepared in reactions of the compound (V) with anacylated Meldrum's acid derivative and a carboxylic acid, the saltthereof, or the reactive derivative thereof. The acylated Meldrum's acidderivative can be prepared according to the methods known in the art,for example, the methods described in Synthesis, p.1213 (1992), and Org.Synth., vol.63, p.198 (1985), with or without slight modifications. Thecarboxylic acid is, for example, a compound represented by the formulaR^(1a)—COCH₂COOH (wherein, R^(1a) has the same meaning as describedabove). Examples of the reactive derivative of the carboxylic acidinclude acid halides (e.g., acid chlorides, acid bromides, etc.); acidamides (e.g., acid amides with pyrazole, imidazole, benzotriazole,etc.,); mixed acid anhydrides [e.g., mono C₁₋₄ alkylcarbonate-mixed acidanhydrides such as monomethylcarbonate, monoethylcarbonate,monoisopropylcarbonate, mono-tert-butylcarbonate; mono-C₇₋₁₀aralkylcarbonate mixed acid anhydrides such as monobenzylcarbonate,mono(p-nitrobenzyl)carbonate, monoallylcarbonate; C₁₋₆ aliphaticcarboxylate mixed acid anhydrides such as acetate, cyanoacetate,propionate, butyrate, isobutyrate, valerate, isovalerate, pivalate,trifluoroacetate, trichloroacetate, acetoacetate; C₇₋₁₁ aromaticcarboxylate mixed acid anhydrides such as benzoate, p-toluate,p-chlorobenzoate, etc.; organic sulfonate mixed acid anhydrides such asmethanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate]; acid azides; activated esters (e.g.,diethoxyphosphoric ester, diphenoxyphosphoric ester, p-nitrophenylester,2,4-dinitrophenylester, cyanomethylester, pentachlorophenylester, esterwith N-hydroxysuccimide, ester with N-hydroxyphthalimide, ester with1-hydroxybenzotriazole, ester with 6-chloro-1-hydroxybenzotriazole,ester with 1-hydroxy-1H-2-pyridone, etc.); and activated thioesters(e.g., 2-pyridylthioester, 2-benzothiazolylthioester, etc.). Theacylated Meldrum's acid derivative and the carboxylic acid or thereactive derivative thereof are used, respectively, in an amount ofabout 1.0 to 10.0 moles, preferably about 1.0 to 2.0 moles per mole ofthe compound (V).

[0092] The reaction may be favorably carried out in a solution using asolvent which is inactive to the reaction. Preferred examples of thesolvent include, but not limited to so far as the reaction can proceed,ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., ketones suchas acetone, methylethylketone, etc., and sulfoxides such asdimethylsulfoxide, etc., or a mixture thereof. In the case where an acidhalide is used as the reactive derivative of the carboxylic acid, thereaction may be carried out in the presence of a deacidifying agent tobe used for the purpose of removing hydrogen halide released from thereaction system. Examples of the deacidifying agent include inorganicbases such as sodium carbonate, potassium carbonate, sodium bicarbonate,etc., aromatic amines such as pyridine, lutidine, etc., and tertiaryamines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc. Thereaction period may vary according to the reagents used and the solvent,but is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours.The reaction temperature is usually 0 to 200° C., preferably 20 to 120°C.

[0093] Instead of using the reactive derivative, the carboxylic acid orthe salt thereof may be reacted directly with the compound (V) in thepresence of a proper condensing agent. Examples of the condensing agentinclude N,N-disubstituted carbodiimides such asN,N-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, etc.,azolides such as N,N-carbonyldiimidazole, etc., dehydrating agents suchas N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorusoxychloride, alkoxyacetylene, etc., and 2-halogenopyridinium salts suchas 2-chloromethyl pyridinium iodide, 2-fluoro-1-methyl pyridiniumiodide, etc. When the condensing agent is used, the reaction seems toproceed via a reactive derivative of carboxylic acid. The carboxylicacid represented by the formula R^(1a)—COCH₂COOH (R^(1a) has the samemeaning as described above) or the reactive derivative thereof is usedin an amount of about 1.0 to 5.0 moles, preferably about 1.0 to 2.0moles per mole of the compound (II).

[0094] The reaction may be favorably carried out in a solution using asolvent which is inactive to the reaction. Preferred examples of thesolvent include, but not limited to so far as the reaction can proceed,ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixture thereof. In the case wherean acid halide is used as the reactive derivative of the carboxylicacid, the reaction may be carried out in the presence of a deacidifyingagent to be used for the purpose of removing hydrogen halide released inthe reaction. Examples of the deacidifying agent include inorganic basessuch as sodium carbonate, potassium carbonate, sodium bicarbonate, etc.,aromatic amines such as pyridine, lutidine, etc., and tertiary aminessuch as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc. Thereaction period may vary according to the reagents used and the solvent,but is usually 30 minutes to 24 hours, preferably 30 minutes to 4 hours.The reaction temperature is usually 0 to 100° C., preferably 0 to 70° C.

[0095] The compound (VII) can be prepared by dehydration cyclization ofthe compound (VI). Examples of catalyst used for the dehydrationreaction include acidic catalysts such as hydrochloric acid, sulfuricacid, phosphoric acid, potassium hydrogensulfate, oxalic acid,p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ethercomplex, etc., and basic catalysts such as sodium hydroxide, potassiumhydroxide, etc., and further include dehydrating agents such as aceticanhydride, N,N-dicyclohexylcarbodiimide, etc., alumina, sodium oxide,phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, etc.The reaction may be favorably carried out in the absence of a solvent orin a solution using a solvent which is inactive to the reaction.Preferred examples of the solvent include, but not limited to so far asthe reaction can proceed, ethers such as diethylether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., sulfoxides such as dimethylsulfoxide, etc., ora mixture thereof. The reaction period is usually 30 minutes to 24hours, preferably 30 minutes to 12 hours. The reaction temperature isusually 0 to 200° C., preferably 0 to 150° C.

[0096] The compound (VIII) can be prepared by a reaction of the compound(VII) with a hydrazine derivative. The hydrazine derivative can beprepared according to methods known in the art, for example, the methodsdescribed in Shin Jikken Kagaku Koza, vol.14, p.1573-1585, Jikken KagakuKoza (4th Ed), vol.20, p.338-342 (Chem. Soc. Japan, Ed.), J. Med. Chem.,vol.28, p.1394 (1985), Eur. J. Med. Chem., vol.24, p.435 (1989), J.Amer. Chem. Soc., vol.81, p.2456 (1990)-229168, Japanese PatentLaid-open Publication No.H02 (1990)-229169, Japanese Patent PublicationNo.S56 (1981)-37231, U.S. Pat. No. 4,260,767, Can. J. Chem., vol.48,p.3554 (1970), J. Chem. Soc., p.3830 (1959), Yakugaku Zasshi, vol.73,p.598 (1953), with or without slight modifications. The hydrazinederivative is used in an amount of about 0.8 to 5.0 moles, preferablyabout 0.9 to 2.0 moles per mole of compound (VII). The reaction may befavorably carried out in a solution using a solvent which is inactive tothe reaction. Preferred examples of the solvent include, but not limitedto so far as the reaction can proceed, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethylether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixture thereof. The reactionperiod may vary according to the reagents used and the solvent, but isusually 30 minutes to 12 hours, preferably 30 minutes to 6 hours. Thereaction temperature is usually 0 to 200° C., preferably 0 to 120° C.

[0097] The compound (VIII) can be prepared, according to reactionformula 3, in the Ullman condensation reaction of the compound (IIIa)with a halogenated benzoic acid derivative, a halogenated picolinic acidderivative, a halogenated nicotinic acid derivative, a halogenatedisonicotinic acid derivative, a halogenated thiphenecarboxylic acid orthe like in the presence of a base. The Ullman condensation reaction canbe carried out according to methods known in the art, for example, themethods described in Chem. Pham. Bull., vol.45, p.719 (1997), OrganicReactions, vol.2, p.243 (1943), vol.14, p.19 (1965), and WO-28446(1996), with or without slight modifications. The halogenated benzoicacid derivative can be prepared according to method known in the art,for example, the methods described in EP389189, Tetrahedron Letters,vol.37, p.2767 (1996), Japanese Patent Laid-open Publication No.S63(1988)-287756, Japanese Patent Laid-open Publication No.H07(1995)-165638, and Collection Czechoslov. Chem. Commun., vol.40, p.719(1975), with or without slight modifications. The halogenated picolinicacid derivative, the halogenated nicotinic acid derivative, and thehalogenated isonicotinic acid derivative can be prepared according tomethod known in the art, for example, the methods described in J. Med.Chem., vol.41, p.1828 (1998), Chem. Pharm. Bull., vol.38, p.2466 (1990),Synth. Commun., vol.27, p.1075 (1997), with or without slightmodifications. The halogenated benzoic acid derivative, the halogenatedpicolinic acid derivative, the halogenated nicotinic acid derivative,the halogenated isonicotinic acid derivative, and the halogenatedthiphenecarboxylic acid are used, respectively, in an amount of about1.0 to 5.0 moles, preferably about 1.0 to 2.0 moles per mole of compound(IIIa). Example of the base include inorganic bases such as sodiumcarbonate, potassium carbonate, sodium bicarbonate, etc., aromaticamines such as pyridine, lutidine, etc., and tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc. The base is used in anamount of about 0.1 to 5.0 moles, preferably about 0.3 to 2.0 moles permole of compound (IIIa). The reaction may be favorably carried out in asolution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, hydrocarbons such as benzene, toluene,cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., and hexamethylphosphoramide, or a mixture thereof. The reactionperiod may vary according to the reagents used and the solvent, but isusually 30 minutes to 24 hours, preferably 30 minutes to 6 hours. Thereaction temperature is usually 0 to 250° C., preferably 20 to 180° C.An additive (an accelerator) may be added into the reaction mixture forthe purpose of increasing the catalytic activity. Preferred examples ofthe additive include powdery copper, copper acetate (II), copper bromide(I), copper bromide (II), copper chloride (I), copper chloride (II),copper iodide (I), copper oxide (I), etc. The additive is used in anamount of about 0.01 to 5.0 moles, preferably about 0.05 to 1.0 molesper mole of compound (IIIa). Examples of the additive also include phasetransfer catalysts and crown ethers. The compound (VIII) may be used inthe following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0098] The compound (IX) can be prepared in a cyclization reaction ofthe compound (VIII) in the presence of an acidic compound known in theart. Examples of the acidic compound include phosphorus oxychloride,phosphorus pentachloride, phosphorus trichloride, thionyl chloride, etc.The acidic compound is used in an amount of about 0.5 to 100 moles,preferably about 1.0 to 30 moles per mole of compound (VIII). Thereaction may be favorably carried out in the absence of a solvent or ina solution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, aromatic hydrocarbons such as benzene, toluene,etc., saturated hydrocarbons such as cyclohexane, hexane, etc., etherssuch as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., amides suchas N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., and sulfoxides such as dimethylsulfoxide,etc., or a mixed solvent thereof. The reaction period is usually 10minutes to 12 hours, preferably 30 minutes to 6 hours. The reactiontemperature is usually 0 to 200° C., preferably 0 to 150° C. Thecompound (IX) thus obtained may be used in the following reaction as itis in the reaction mixture or as a crude product, but also isolated fromthe reaction mixture by the common methods, and can be easily purifiedby separation means such as recrystallization, distillation,chromatography, etc.

[0099] The compound (Ia; X═O, R^(2a)═H) can be prepared in a cyclizationreaction known in the art of the compound (VIII). The reaction can becarried out, for example, according to methods, for example, by heatingand by the use of an acidic compound, by halogenation and subsequentcyclization in the presence of Lewis acid, or the modified methodthereof.

[0100] In the case where the cyclization is conducted by heating, thereaction may be favorably carried out in the absence of a solvent or ina solution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, high-boiling point hydrocarbons such as1,2,3,4-tetrahydronaphthalene, etc., and high-boiling point ethers suchas diphenylether, diethyleneglycol dimethylether, etc., or a mixturethereof. The reaction period is usually 10 minutes to 24 hours,preferably 10 minutes to 6 hours. The reaction temperature is usually100 to 300° C., preferably 100 to 250° C.

[0101] In the case where an acidic compound is used for cyclization, anacidic compound, e.g., methanesulfonic acid, phosphorus pentoxide,phosphorus oxychloride, phosphorus pentachloride, phosphorustrichloride, thionyl chloride, hydrochloric acid, sulfuric acid,polyphosphoric acid, p-toluenesulfonic acid, etc., or a mixture thereofis commonly used. The acidic compound is used in an amount of about 0.5to 100 moles, preferably about 1.0 to 20 moles per mole of compound(VIII). The reaction may be favorably carried out in the absence of asolvent or in a solution using a solvent which is inactive to thereaction. Preferred examples of the solvent include, but not limited toso far as the reaction can proceed, aromatic hydrocarbons such asbenzene, toluene, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., acid anhydrides such as acetic anhydride, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixture thereof. The reactionperiod is usually 5 minutes to 12 hours, preferably 10 minutes to 3hours. The reaction temperature is usually 0 to 250° C., preferably 0 to150° C.

[0102] In the case where the compound (VIII) is halogenated andsubsequently cyclized in the presence of a Lewis acid, examples of thehalogenating agent to be used include thionyl halides such as thionylchloride, thionyl bromide, etc., phosphoryl halides such as phosphorylchloride, phosphoryl bromide, etc., phosphorus halides such asphosphorus pentachloride, phosphorus trichloride, phosphoruspentabromide, phosphorus tribromide, etc., oxalyl halides such as oxalylchloride, etc., phosgene, etc. The halogenating agent is used in anamount of about 1.0 to 30 moles, preferably about 1.0 to 10 moles permole of compound (VIII). The reaction may be favorably carried out inthe absence of a solvent or in a solution using a solvent which isinactive to the reaction. Preferred examples of the solvent include, butnot limited to so far as the reaction can proceed, aromatic hydrocarbonssuch as benzene, toluene, etc., saturated hydrocarbons such ascyclohexane, hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., and halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., or a mixture thereof. The reaction period is usually 10 minutes to12 hours, preferably 10 minutes to 6 hours. The reaction temperature isusually −10 to 200° C., preferably −10 to 120° C. The product may beused in the following reaction as it is in the reaction mixture or as acrude product, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc. Examples of theLewis acid used in the following cyclization reaction include anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride,etc. The Lewis acid is used in an amount of about 0.1 to 20 moles,preferably about 0.2 to 5.0 moles per mole of compound (VIII). Thereaction may be favorably carried out in the absence of a solvent or ina solution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, aromatic hydrocarbons such as benzene, toluene,etc., and halogenated hydrocarbons such as monochlorobenzene,o-dichlorobenzene, 1,2,4-trichlorobenzene, dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane, or a mixture thereof. Thereaction period is usually 30 minutes to 12 hours, preferably 30 minutesto 6 hours. The reaction temperature is usually −20 to 200° C.,preferably −5 to 120° C. The product (Ia; X═O, R^(2a)═H) of thecyclization reaction described above may be used in the followingreaction as it is in the reaction mixture or as a crude product, butalso isolated from the reaction mixture by the common methods, and canbe easily purified by separation means such as recrystallization,distillation, chromatography, etc.

[0103] The compound (Ia; X═O, R^(2a)═H) can be prepared in a hydrolysisreaction known in the art in the presence of an acid or a base of thecompound (IX), or according to methods known in the art, for example,the method described in U.S. Pat. No. 5,459,146 (1995), and J. Org.Chem., vol.38, p.3740 (1973), with or without slight modifications.Examples of the acid used for the acid-catalyzed hydrolysis includemineral acids such as hydrochloric acid, sulfuric acid, etc., Lewisacids such as boron trichloride, boron tribromide, etc., a mixture of aLewis acid and a thiol or a sulfide, and organic acids such astrifluoroacetic acid, p-toluenesulfonic acid, etc. are commonly used asthe catalyst. Examples of the base used for the base-catalyzedhydrolysis include metal hydroxides such as sodium hydroxide, potassiumhydroxide, barium hydroxide, etc., metal carbonates such as sodiumcarbonate, potassium carbonate, etc., metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium tert-butoxide, etc., and organicbases such as triethylamine, imidazole, formamidine, etc. are commonlyused as the catalyst. The acid and the base are used, respectively, inan amount of about 0.5 to 100 moles, preferably about 0.5 to 10 molesper mole of compound (IX). The reaction may be favorably carried out inthe absence of a solvent or in a solution using a solvent which isinactive to the reaction. Preferred examples of the solvent include, butnot limited to so far as the reaction can proceed, alcohols such asmethanol, ethanol, propanol, etc., aromatic hydrocarbons such asbenzene, toluene, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., organic acids such as formic acid, acetic acid, etc.,ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitriles such as acetonitrile, propionitrile, etc., ketones suchas acetone, methylethylketone, etc., sulfoxides such asdimethylsulfoxide, etc., and water, etc., or a mixture thereof. Thereaction period is usually 10 minutes to 60 hours, preferably 10 minutesto 12 hours. The reaction temperature is usually −10 to 200° C.,preferably 0 to 150° C. The product (Ia; X═O, R^(2a)═H) may be used inthe following reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0104] The compound (Ia) having hydrogen as X^(a) can be prepared bysubjecting the compound (IX) to a catalytic reduction reaction in thepresence of a variety of catalysts under hydrogen atmosphere. Examplesof the catalyst used include platinum oxide, platinum on activatedcarbon, palladium on activated carbon, palladium on barium sulfate,nickel, copper-chromium oxide, rhodium, cobalt, ruthenium, etc. Thecatalyst is used in an amount of about 1.0 to 1000% by weight,preferably about 5.0 to 300% by weight per the compound (VI). Thereaction may be favorably carried out in a solution using a solventwhich is inactive to the reaction. Preferred examples of the solventinclude, but not limited to so far as the reaction can proceed, alcoholssuch as methanol, ethanol, propanol, etc., ethers such as diethylether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., saturatedhydrocarbons such as cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., organic acids suchas formic acid, acetic acid, etc., and water, etc., or a mixturethereof. The reaction period may vary according to activity and quantityof the catalyst used, but is usually 30 minutes to 24 hours, preferably30 minutes to 6 hours. The reaction temperature is usually 0 to 120° C.,preferably 20 to 80° C. The reaction pressure is usually 1 to 100 atm.An additive (an accelerator) may be added into the reaction mixture forthe purpose of increasing the catalytic activity. Preferred examples ofthe acidic additive include inorganic acids such as hydrochloric acid,sulfuric acid, nitric acid, perchloric acid, hydrobromic acid,phosphoric acid, etc., and organic acids such as acetic acid,trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaricacid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Preferred examplesof the basic additive include sodium hydroxide, potassium hydroxide,etc. The compound (Ia) thus obtained may be used in the followingreaction as it is in the reaction mixture or as a crude product, butalso isolated from the reaction mixture by the common methods, and canbe easily purified by separation means such as recrystallization,distillation, chromatography, etc.

[0105] The compound (Ia) having nitrile as X^(a) can be prepared in areaction of the compound (IX) with a metal cyanide [e.g., sodiumcyanide, potassium cyanide, or copper cyanide (I)] orbenzyltrimethylammonium cyanide. The metal cyanide orbenzyltrimethylammonium cyanide is used in an amount of about 1.0 to 5.0moles, preferably about 1.0 to 2.0 moles per mole of compound (IX). Thereaction may be favorably carried out in a solution using a solventwhich is inactive to the reaction. Preferred examples of the solventinclude, but not limited to so far as the reaction can proceed,hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc., amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., andhexamethylphosphoramide or a mixture thereof. The reaction period mayvary according to the reagents used and the solvent, but is usually 30minutes to 24 hours, preferably 30 minutes to 8 hours. The reactiontemperature is usually 0 to 250° C., preferably 20 to 180° C. Anadditive (an accelerator) may be added into the reaction mixture for thepurpose of increasing the catalytic activity. Examples of the additiveinclude sodium iodide, phase transfer catalysts, crown ethers. Thecompound (Ia) thus obtained may be used in the following reaction as itis in the reaction mixture or as a crude product, but also isolated fromthe reaction mixture by the common methods, and can be easily purifiedby separation means such as recrystallization, distillation,chromatography, etc.

[0106] The compound (Ia) having an alkyl group as X^(a) can be preparedin a reaction of the compound (IX) with a corresponding alkylating agentknown in the art (e.g., Grignard reagents, organolithium reagents,organocerium reagents, organotitanium reagents, organozinc reagents,organoaluminum reagents, and organocopper reagents). The alkylatingagent is used in an amount of about 0.8 to 20 moles, preferably about1.0 to 5.0 moles per mole of compound (IX). Examples of the solvent usedfor dilution include, but not limited to so far as the reaction canproceed, aromatic hydrocarbons such as benzene, toluene, etc., saturatedhydrocarbons such as cyclohexane, hexane, etc., halogenated hydrocarbonssuch as chlorotoluene, etc., and ethers such as tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., or a mixture thereof. The reactionperiod is usually 10 minutes to 20 hours, preferably 15 minutes to 6hours. The reaction temperature is usually −20 to 150° C., preferably 0to 100° C. The compound (Ia) thus obtained may be used in the followingreaction as it is in the reaction mixture or as a crude product, butalso isolated from the reaction mixture by the common methods, and canbe easily purified by separation means such as recrystallization,distillation, chromatography, etc.

[0107] The compound (Ia) having an alkoxy group as X^(a) or a hydroxylgroup as X^(a) and an alkyl group as R^(2a) can be prepared in areaction of the compound (Ia; X═O, R^(2a)═H) with a correspondingalkylating agent (e.g., substituted alkyl halides, substituted alcoholsulfonic esters, etc.) in the presence of a base. The alkylating agentis used in an amount of about 1.0 to 100 moles, preferably about 1.0 to30 moles per mole of the compound (Ia; X═O, R^(2a)═H). Example of thebase include inorganic bases such as sodium carbonate, potassiumcarbonate, sodium bicarbonate, etc., aromatic amines such as pyridine,lutidine, etc., and tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc., metal hydrides such assodium hydride, potassium hydride, etc., metal amides such as sodiumamide, lithium diisopropylamide, lithium hexamethyldisilazide, etc., andmetal alkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide, etc. The base is used in an amount of about 1.0 to 10moles, preferably about 1.0 to 3.0 moles per mole of the compound (Ia;X═O, R^(2a)═H). The reaction may be favorably carried out in a solutionusing a solvent which is inactive to the reaction. Preferred examples ofthe solvent include, but not limited to so far as the reaction canproceed, ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., nitrites such as acetonitrile, propionitrile, etc., and sulfoxidessuch as dimethylsulfoxide, etc., or a mixture thereof. The reactionperiod is usually 30 minutes to 72 hours, preferably 1 to 24 hours. Thereaction temperature is usually −20 to 200° C., preferably 0 to 150° C.The compound (Ia) may be used in the following reaction as it is in thereaction mixture or as a crude product, but also isolated from thereaction mixture by the common methods, and can be easily purified byseparation means such as recrystallization, distillation,chromatography, etc.

[0108] The compound (Ia) having an amino group as X^(a) can be preparedin a reaction of the compound (IX) with sodium azide and by subsequentcatalytic reduction of the resulting azide. Sodium azide is used in anamount of about 0.8 to 10 moles, preferably about 1.0 to 3.0 moles permole of compound (IX). The reaction may be favorably carried out in asolution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, ethers such as diethylether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., pyridine, hydrocarbons such asbenzene, toluene, cyclohexane, hexane, etc., halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., and sulfoxides such as dimethylsulfoxide,etc., or a mixture thereof. The reaction period is usually 5 minutes to12 hours, preferably 10 minutes to 3 hours. The reaction temperature isusually 0 to 200° C., preferably 20 to 150° C. The azide derivative thusobtained may be used in the following reaction as it is in the reactionmixture or as a crude product, but also isolated from the reactionmixture by the common methods, and can be easily purified by separationmeans such as recrystallization, distillation, chromatography, etc.

[0109] The compound (Ia) can be prepared by subjecting the azide thusobtained to a catalytic reduction reaction in the presence of a varietyof catalysts under hydrogen atmosphere. Examples of the catalyst usedinclude platinum oxide, platinum on activated carbon, palladium onactivated carbon, palladium on barium sulfate, nickel, copper-chromiumoxide, rhodium, cobalt, ruthenium, etc. The catalyst is used in anamount of about 1.0 to 1000% by weight, preferably about 5.0 to 300% byweight per the compound (IX). The reaction may be favorably carried outin a solution using a solvent which is inactive to the reaction.Preferred examples of the solvent include, but not limited to so far asthe reaction can proceed, alcohols such as methanol, ethanol, propanol,etc., ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., saturated hydrocarbons such as cyclohexane,hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., organic acids such as formic acid, aceticacid, etc., and water, etc., or a mixture thereof. The reaction periodmay vary according to the activity and the quality of the catalyst usedand the solvent, but is usually 30 minutes to 24 hours, preferably 30minutes to 6 hours. The reaction temperature is usually 0 to 120° C.,preferably 20 to 80° C. The reaction pressure is usually 1 to 100 atm.An additive (an accelerator) may be added into the reaction mixture forthe purpose of increasing the catalytic activity. Preferred examples ofthe acidic additive include inorganic acids such as hydrochloric acid,sulfuric acid, nitric acid, perchloric acid, hydrobromic acid,phosphoric acid, etc., and organic acids such as acetic acid,trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaricacid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Preferred examplesof the basic additive include sodium hydroxide, potassium hydroxide,etc. The compound (Ia) thus obtained may be used in the followingreaction as it is in the reaction mixture or as a crude product, butalso isolated from the reaction mixture by the common methods, and canbe easily purified by separation means such as recrystallization,distillation, chromatography, etc.

[0110] The compound (Ia) having a substituted alkylthio group as X^(a)can be prepared by treating the compound (Ia; X═O, R^(2a)═H) in thepresence of a sulfidizing agent (e.g., phosphorus pentasulfide,Lawesson's reagent, Davy reagent) and by subjecting the resultingcompound to an alkylation reaction subsequently. The sulfidizing agentis used in an amount of about 0.5 to 10 moles, preferably about 1.0 to3.0 moles per mole of the compound (Ia; X═O, R^(2a)═H). The reaction maybe favorably carried out in a solution using a solvent which is inactiveto the reaction. Preferred examples of the solvent include, but notlimited to so far as the reaction can proceed, ethers such asdiethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,aromatic amines such as pyridine, lutidine, etc., hydrocarbons such asbenzene, toluene, cyclohexane, hexane, etc., halogenated hydrocarbonssuch as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., nitrites such as acetonitrile, propionitrile,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixturethereof. The reaction period is usually 30 minutes to 24 hours,preferably 1 to 12 hours. The reaction temperature is usually 0 to 200°C., preferably 0 to 150° C. The compound (Ia) may be used in thefollowing reaction as it is in the reaction mixture or as a crudeproduct, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0111] The compound (Ia) having a substituted alkoxy group or asubstituted alkylthio group as X^(a) can be prepared in a reaction ofthe compound (IX) with a substituted alkyl alcohol or a substitutedalkyl thiol in the presence of a base. The substituted alkyl alcohol andthe substituted alkyl thiol are used, respectively, in an amount ofabout 1.0 to 50.0 moles, preferably about 1.0 to 30.0 moles per mole ofthe compound (IX). Example of the base include inorganic bases such assodium carbonate, potassium carbonate, sodium bicarbonate, etc., metalhydrides such as sodium hydride, potassium hydride, etc., metal amidessuch as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., and metal alkoxides such as sodiummethoxide, sodium ethoxide, potassium tert-butoxide, etc. The base isused in an amount of about 1.0 to 50.0 moles, preferably about 1.0 to 15moles per mole of compound (IX). The reaction may be favorably carriedout in a solution using a solvent which is inactive to the reaction.Preferred examples of the solvent include, but not limited to so far asthe reaction can proceed, ethers such as diethylether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, etc., and sulfoxides such as dimethylsulfoxide,etc., or a mixture thereof. The reaction period is usually 10 minutes to48 hours, preferably 15 minutes to 12 hours. The reaction temperature isusually 0 to 200° C., preferably 40 to 120° C. The compound (Ia) may beused in the following reaction as it is in the reaction mixture or as acrude product, but also isolated from the reaction mixture by the commonmethods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0112] The compound (Ia) having a sulfinyl group as X^(a) can beprepared by oxidizing the corresponding sulfide compound (Ia). Examplesof the oxidizing agent include hydrogen peroxide, peracids such asperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc., sodiummetaperiodate, hydroperoxide, ozone, selenium dioxide, chromic acid,dinitrogen tetraoxide, acyl nitrate, iodine, bromine,N-bromosuccinimide, iodosylbenzene, sulfuryl chloride and silica gelhydrate, tert-butyl hypochlorite, etc. The oxidizing agent is used in anamount of about 0.5 to 5.0 moles, preferably about 1.0 to 1.5 moles permole of the compound (Ia). The reaction may be favorably carried out ina solution using a solvent which is inactive to the reaction. Preferredexamples of the solvent include, but not limited to so far as thereaction can proceed, alcohols such as methanol, ethanol, propanol,etc., ethers such as diethylether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., ketones such as acetone, methylethylketone,etc., hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc., sulfoxides such asdimethylsulfoxide, etc., organic acids such as formic acid, acetic acid,etc., and water, etc., or a mixture thereof. The reaction period isusually 5 minutes to 48 hours, preferably 10 minutes to 12 hours. Thereaction temperature is usually −40 to 200° C., preferably −10 to 120°C. The compound (Ia) may be used in the following reaction as it is inthe reaction mixture or as a crude product, but also isolated from thereaction mixture by the common methods, and can be easily purified byseparation means such as recrystallization, distillation,chromatography, etc.

[0113] The compound (Ia) having a substituted alkyl amino group as X^(a)can be prepared in a reaction of the compound (IX) with a substitutedalkylamine, in the presence of a base if desired. The substitutedalkylamine is used in an amount of about 1.0 to 1000 moles, preferablyabout 1.0 to 200 moles per mole of compound (IX). Example of the baseinclude inorganic bases such as sodium carbonate, potassium carbonate,sodium bicarbonate, etc., aromatic amines such as pyridine, lutidine,etc., and tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc. The base is used in an amount of about 0.1 to50 moles, preferably about 1.0 to 10 moles per mole of compound (IX).The reaction may be favorably carried out in the absence of a solvent orin a solution using a solvent which is inactive to the reaction.Preferred examples of the solvent include, but not limited to so far asthe reaction can proceed, alcohols such as methanol, ethanol, propanol,etc., hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, etc., nitrites such as acetonitrile,propionitrile, etc., and water, etc., or a mixture thereof. The reactionperiod may vary according to the reagents used and the solvent, but isusually 10 minutes to 48 hours, preferably 30 minutes to 20 hours. Thereaction temperature is usually 0 to 250° C., preferably 20 to 150° C.In the case where a reaction reagent has a low boiling point, thesubstitution reaction can be carried out in a similar condition byheating and stirring the reaction mixture under pressure, for example inan autoclave. The compound (Ia) may be used in the following reaction asit is in the reaction mixture or as a crude product, but also isolatedfrom the reaction mixture by the common methods, and can be easilypurified by separation means such as recrystallization, distillation,chromatography, etc.

[0114] The compound (Ia) having a cycloalkane ring as ring B^(a) can beprepared in a reaction of the compound (IIIa) in the presence of anacidic compound, with an 2-oxocycloalkanecarboxylic ester represented bythe formula (X).

[0115] [wherein, R″ is a hydrocarbon group which may be optionallysubstituted; and ring B^(ab) is a 5- to 7-membered cycloalkane ringwhich may be optionally substituted]. In the case where an acidiccompound is used for cyclization, an acidic compound, e.g., phosphorusoxychloride, phosphorus pentachloride, phosphorus trichloride, thionylchloride, hydrochloric acid, sulfuric acid, polyphosphoric acid,p-toluenesulfonic acid, or the like, is used. The acidic compound isused in an amount of about 0.5 to 200 moles, preferably about 5.0 to 50moles per mole of compound (IIIa), or about 1.0 to 10000% by weight,preferably about 2.0 to 1000% by weight. The reaction may be favorablycarried out in the absence of a solvent or in a solution using a solventwhich is inactive to the reaction. Preferred examples of the solventinclude, but not limited to so far as the reaction can proceed, aromatichydrocarbons such as benzene, toluene, etc., saturated hydrocarbons suchas cyclohexane, hexane, etc., ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc., and sulfoxides such as dimethylsulfoxide, etc., or a mixturethereof. The reaction period is usually 30 minutes to 12 hours,preferably 30 minutes to 6 hours. The reaction temperature is usually 0to 200° C., preferably 0 to 150° C. The compound (Ia) thus obtained maybe used in the following reaction as it is in the reaction mixture or asa crude product, but also isolated from the reaction mixture by thecommon methods, and can be easily purified by separation means such asrecrystallization, distillation, chromatography, etc.

[0116] The compounds (IIa) and (IIIa) can be prepared according to themethod similar to those for the compounds (II) and (III).

[0117] The compounds (I) and (Ia) can also be prepared in the reactionprocesses described above in combination with another or 2 or more otherreactions known in the art, including hydrolysis, deprotection,acylation, alkylation, hydrogenation, oxidation, reduction, carbon chainelongation, and exchange of substituent group. These reactions can becarried out according to the methods, described, for example, in “ShinJikken Kagaku Koza, vol.14 and 15 (Chem. Soc. Japan, Ed.), 1977, and1978”.

[0118] In each of the reactions of the present invention described aboveand of reactions for preparing a raw compounds, if the starting compoundhas amino, carboxyl, or hydroxyl groups as the substituents thereof,each of these groups may be protected by a protecting group commonlyused in peptide chemistry, and the protecting group can be removed afterthe reaction to obtain the desired compound is completed.

[0119] Examples of the protecting group for an amino group include aformyl group, C₁₋₆ alkylcarbonyl groups (e.g., acetyl, ethylcarbonyl,etc.), C₁₋₆ alkyloxycarbonyl groups (e.g., methoxycarbonyl,ethoxycarbonyl, etc.), a benzoyl group, C₇₋₁₀ aralkyl-carbonyl groups(e.g., benzylcarbonyl, etc.), a trityl group, a phthaloyl group, aN,N-dimethylaminomethylene group, etc. These groups may be furthersubstituted by 1 to 3 substituents such as halogen atoms (e.g.,fluorine, chlorine, bromine, iodine, etc.) and a nitro group.

[0120] Examples of the protecting group for a carboxyl group includeC₁₋₆ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, etc.), a phenyl group, a trityl group, a silyl group, etc.These groups may be further substituted by 1 to 3 substituents includinghalogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), aformyl group, C₁₋₆ alkyl-carbonyl groups (e.g., acetyl, propionyl,butylcarbonyl, etc.), a nitro group, etc.

[0121] Examples of the protecting group for a hydroxyl group includeC₁₋₆ alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, etc.), a phenyl group, C₇₋₁₀ aralkyl groups (e.g., benzyl,etc.), C₁₋₆ alkyl-carbonyl groups (e.g., acetyl, propionyl, etc.), abenzoyl group, C₇₋₁₀ aralkyl-carbonyl groups (e.g., benzylcarbonyl,etc.), a tetrahydropyranyl group, a tetrahydrofuranyl group, a silylgroup, etc. These groups may be further substituted by 1 to 3substituents including halogen atoms (e.g., fluorine, chlorine, bromine,iodine, etc.), C₁₋₆ alkyl groups (e.g., methyl, ethyl, propyl, etc.), aphenyl group, C₇₋₁₀ aralkyl groups (e.g., benzyl, etc.), a nitro group,etc.

[0122] Removal of the protecting group can be performed according tomethods known in the art or the modified methods thereof, for example,methods by the use of an acid, a base, a reducing agent, UV light,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, and palladium acetate, etc.

[0123] The compounds, (I), (I′), (Ia) and (Ia′), of the presentinvention can be isolated and purified according to methods known in theart, such as solvent extraction, liquid conversion, solvent exchange,crystallization, recrystallization, chromatography, etc. The startingcompounds or the salts thereof of the compound (I), (I′), (Ia) and (Ia′)of the present invention may be isolated and purified according to themethods known in the art described above, or used in the followingprocess as they are in the reaction mixtures without isolation.

[0124] In the case where the compounds (I), (I′), (Ia) and (Ia′) arepurified by recrystallization, solvents which may be used for therecrystallization are, for example, water, alcohols (e.g., methanol,ethanol, n-propanol, isopropanol, etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g.,hexane, heptane, cyclohexane, etc.), ethers (e.g., diethylether,isopropylether, tetrahydrofuran, dioxane, etc.), ketones (e.g., acetone,methylethylketone, etc.), nitrites (e.g., acetonitrile, etc.),sulfoxides (e.g., dimethylsulfoxide, etc.), acid amides (e.g.,N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.),carboxylic acids (e.g., acetic acid, propionic acid, etc.), etc. Thesesolvents may be used as a single solvent, or a mixture of 2 solvents inan appropriate proportion of, for example, 1:1 to 1:10, or a mixture ofmore solvents.

[0125] When a desired product is obtained as a free state, the desiredproduct may be converted to the salt or the hydrate according to commonmethods, meanwhile when a product is obtained as a salt or a hydrate,the product may be converted to the free state or another salt thereof.The compounds (I), (I′), (Ia) and (Ia′) thus obtained can be isolatedfrom the reaction solution and purified according to methods known inthe art, for example, solvent exchange, concentration, solventextraction, distillation, crystallization, recrystallization,chromatography, etc.

[0126] When the compounds (I), (I′), (Ia) and (Ia′) are present as amixture of configurational isomers, diastereomers, conformers, etc.,desired isomers or conformers can be isolated according to isolation andpurification means described above if desired. Further, when thecompounds (I), (I′), (Ia) and (Ia′) are optically active compounds, +and − optical isomers can be separated according to optical separationmeans commonly practiced.

[0127] The compound (I) of the present invention or the salt thereof isuseful as a preventive and therapeutic agent of a variety of diseases ofhuman and animals (such as mouse, rat, guinea pig, cat, dog, sheep,horse, cow, monkey, etc.), including diseases associated with allergicreactions, autoimmune diseases (e.g., allergic asthma, atopicdermatitis, urticaria, allergic conjunctivitis, allergic rhinitis,pollinosis, chronic rheumatoid arthritis, systemic lupus erythematosus,multiple sclerosis, chronic obstructive pulmonary diseases, malignantanaemia, idiopathic thrombocytopenic purpura, myasthenia gravis,pachyderms, uveitis, chronic thyroiditis, Sjoegren's syndromes,Addison's disease, Basedow's disease, agranulocytosis, etc.), shocks(e.g., septic shock, anaphylactic shock, adult respiratory distresssyndromes, etc.), arteriosclerosis, thrombotic diseases, ischemicdiseases (e.g., ischemic heart diseases, ischemic brain diseases,cardiac infarction, angina pectoris, etc.), cerebrovascular convulsion,erosive arthritis, polymyositis, ileus, organ failures induced byprogress of the shocks and the like (e.g., lung failure, renal failure,hepatic failure, gut hemorrhage, etc.), etc., and as a preventive andtherapeutic agent for graft rejections or graft versus host diseasesassociated with organ transplantation.

[0128] The compound (I) of the present invention is low in toxicity, andthus can be safely administered, as it is or as it is mixed with apharmaceutically acceptable carrier according to methods known in theart, as a pharmaceutical composition in a variety of forms, such astablets (including sugar coated tablet, film coated tablet), powder,granule, capsule (including soft capsule), liquid, injection,suppository, sustained-release drug, patch, etc., and furthermore aschewing gum, etc., orally or parenterally (e.g., local, rectal,intravenous administration, etc.). The content of the compound (I) ofthe present invention in the composition is about 0.01 to 100% by weightof the composition. The dosage may vary according to the administrationobject, the administration route, and the disease, but is, for example,about 0.1 to 100 mg/kg body weight, preferably about 0.2 to 50 mg/kgbody weight, more preferably about 0.5 to 30 mg/kg body weight as thecompound (I) when the composition is administered orally, and thecomposition may be administered once a day or divided several times aday.

[0129] The compound (I) or the salt thereof can be used as a preventiveand therapeutic agent for a variety of diseases owing to its excellentCOX inhibitory activity. For example, the pharmaceutical composition ofthe present invention can be used as a preventive and therapeutic agentfor diseases including inflammatory diseases (e.g., diabeticcomplications such as algesic fervescence, retinopathy, nephropathy,nerve disorders, great vessel disorder, etc.; arthritides such asrheumatism, chronic rheumatism, osteoarthritis, rheumatoid myelitis,urarthritis, periostitis, etc.; lumbago; gout; postoperative andposttraumatic inflammation; remission of puffiness; neuralgia;pharyngitis; cystitis; chronic hepatitis; acute pancreatitis; chronicpancreatitis; Crohn disease; inflammatory enteropathy such as ulcerativecolitis, etc.; meningitides; inflammatory ophthalmic diseases;inflammatory pulmonary diseases such as pneumonia, silicosis, pulmonarysarcoidosis, tuberculosis, etc., etc.); allergic diseases (e.g., asthma,atopic dermatitis, chronic obstructive pulmonary diseases, etc.);supraneural disorders (e.g., cerebrovascular diseases such as cerebralhemorrhage and brain infarction, etc., cephalic trauma, spine damage,brain edema, multiple sclerosis, etc.); neurodegenerative diseases(e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, AIDS encephalopathy, etc.); systemic erythematosus;psoriasis; bladder cancer; breast cancer; uterocervical cancer; chroniclymphemia; chronic myelocytic leukemia; colon cancer; colic cancer;rectal cancer; Helicobacter pylori infection disease; Hodgkin disease;insulin-dependent diabetes; malignant melanoma; multiple myeloma;non-Hodgkin's lymphoma; non-small cell lung cancer; ovarian cancer;peptic ulcer; prostatic cancer; infertility; Behet's disease; systemicfungal infection disease; acute bacteria meningitides; acute myocardialinfarction; acute viral encephalitis; adult respiratory distresssyndrome; bacteria pneumonia; herpes simplex virus infection disease;varicella zoster virus infection disease; AIDS; human papilloma virusinfection disease; influenza; invasive staphylococcal infection disease;septicaemia; interstitial hepatic disease situational ileitis;circulatory diseases (e.g., angina pectoris, cardiac infarction, staticcardiac failure, disseminated intravascular coagulation syndrome,arteriosclerosis, peripheral vascular diseases, etc.); etc.

[0130] When the compound (I) is used for prevention and treatment of avariety of diseases using its COX inhibitory activity, the compound (I)of the present invention may be safely administered as a pharmaceuticalcomposition containing a pharmaceutically acceptable carrier, formulatedin a similar manner as described above. The dosage may be vary accordingto the administration object, the administration route, and the disease,but, is, for example, is about 0.1 to 20 mg/kg body weight, preferablyabout 0.2 to 10 mg/kg body weight, more preferably about 0.5 to 10 mg/kgbody weight as the compound (I) when the composition is administeredorally, and the composition may be administered once a day or dividedseveral times a day.

[0131] Examples of the pharmaceutically acceptable carrier used for theproduction of the pharmaceutical composition of the present inventioninclude various organic or inorganic carriers commonly used for suchformulations, for example, diluents, lubricants, binders, disintegrants,etc., for solid formulations, and solvents, solubilizing agents,suspending agents, isotonic agents, buffer agents, smoothing agents,etc., for liquid formulations. Additionally, other additives may also beused, if desired, such as antiseptic substances, antioxidants, coloringagents, sweeteners, absorbents, humectants, as well as the carriersabove.

[0132] Examples of the diluent include lactose, sucrose, D-mannitol,starch, cornstarch, crystalline cellulose, light silica anhydrate, etc.

[0133] Examples of the lubricant include magnesium stearate, calciumstearate, talc, colloidal silica, etc.

[0134] Examples of the binder include crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcelulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium, etc.

[0135] Examples of the disintegrant include starch,carboxymethylcellulose, carboxymethylcellulose calcium, sodiumcroscarmellose, carboxymethylstarch sodium, L-hydroxypropylcellulose,etc.

[0136] Examples of the solvent include injection solvents, alcohol,propyleneglycol, macrogol, benne oil, corn oil, olive oil, etc.

[0137] Examples of the solubilizing agent include polyethyleneglycol,propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

[0138] Examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate, etc, and hydrophilic polymers such as polyvinylalcohol,polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,etc.

[0139] Examples of the isotonic agent include glucose, D-sorbitol,sodium chloride, glycerol, D-mannitol, etc.

[0140] Examples of the buffer agent include buffer solutions of thesalts such as phosphate, acetate, carbonate, citrate, etc.

[0141] Examples of the smoothing agent include benzyl alcohol, etc.

[0142] Examples of the antiseptic substance include paraoxybenzoateesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid, sorbic acid, etc.

[0143] Examples of the antioxidant include sulfites, ascorbic acid,α-tocopherol, etc.

[0144] Hereinafter, the present invention is described in more detail byreference to Reference Examples, Examples and Formulation Examples andExperimental Examples, which however are not intended to limit thepresent invention, and may be modified within the scope of the presentinvention.

[0145] The term “room temperature” in the following Reference Examplesand Examples refers to a temperature of about 10 to 35° C. The term “%”refers to % by weight unless it is explicitly indicated otherwise.Silica gel used is Kieselgel 60, 0.063-0.200 mm (Merck) unless it isexplicitly indicated otherwise, and basic silica gel is ChromatorexNH-DM1020, 0.100-0.200 mm, (Fuji Silysia Chemical).

[0146] The meanings of abbreviations used in the description are asfollows

[0147] s: singlet

[0148] d: doublet

[0149] t: triplet

[0150] q: quartet

[0151] m: multiplet

[0152] br: broad

[0153] J: coupling constant

[0154] Hz: Hertz

[0155] CDCl₃: deuterated chloroform

[0156] DMSO-d₆: deuterated dimethylsulfoxide

[0157] NMR: Proton Nuclear Magnetic Resonance

Reference Example 1-1

[0158] 3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine

[0159] To an ice-cold solution of aminocrotonitrile (82 g, 1.0 mol) and2-hydrazinopyridine (120 g, 1.1 mol) in ethanol (300 mL) was addedacetic acid (132 g, 2.2 mol), and the mixture was heated under refluxfor 3.5 hours. After the mixture was allowed to cool to roomtemperature, the reaction solvent was evaporated under reduced pressureand water was added to the residue. After the solution was made basic bythe addition of an aqueous sodium hydroxide solution, organic matter wasextracted with ethyl acetate. The extract was washed with saturatedbrine and water and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. Purification of theresidue by silica gel column chromatography (ethyl acetate) gave thetitle compound (156.3 g, 90% yield).

[0160] mp: 103-104° C. (recrystallized from ethyl acetate).

[0161] NMR (CDCl₃) δ: 2.25 (3H, s), 5.37 (1H, s), 5.92 (2H, br s), 7.07(1H, m), 7.76 (1H, m), 7.94 (1H, d, J=7.0 Hz), 8.32 (1H, d, J=6.0 Hz).

Reference Example 1-2

[0162] Diethyl2-([[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]methylene)malonate

[0163] A mixture of diethyl ethoxymethylenemalonate (32.5 g, 0.15 mol)and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (23.8 g, 0.137 mol) washeated under reflux at 120° C. for 1 hour. After the mixture was allowedto cool to room temperature, the reaction solvent was evaporated underreduced pressure. The crude crystals thus obtained were filtered andwashed with diethylether to give the title compound (45 g, 96% yield).

[0164] mp: 128-131° C. (recrystallized from ethyl acetate/hexane).

[0165] NMR (CDCl₃) δ: 1.33 (3H, t, J=7.0 Hz), 1.39 (3H, t, J=7.0 Hz),2.31 (3H, s), 4.27 (2H, q, J=7.0 Hz), 4.38 (2H, q, J=7.0 Hz), 6.03 (1H,s), 7.13-7.23 (1H, m), 7.77-7.96 (2H, m), 8.25 (1H, d, J=13.9 Hz),8.49-8.56 (1H, m), hidden (1H).

[0166] Elementary Analysis: for C₁₇H₂₀N₄O₄

[0167] Calcd.: C, 59.29; H, 5.85; N, 16.27.

[0168] Found: C, 59.31; H, 5.91; N, 16.38.

Reference Example 1-3

[0169] Ethyl2-benzoyl-3-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-propenoate

[0170] Following the procedure described in Reference Example 1-2, thetitle compound was prepared from3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine and ethyl2-benzoyl-3-ethoxy-2-propenoate (91% yield).

[0171] mp: 94-97° C. (recrystallized from methanol).

[0172] NMR (CDCl₃) δ: 0.94, 0.96 (3H, t, J=7.0 Hz), 2.31, 2.31 (3H, s),4.04, 4.12 (2H, q, J=7.0 Hz), 6.02, 6.14 (1H, s), 7.15-8.30 (9H, m),8.53-8.70 (1H, m), hidden (1H).

Reference Example 1-4

[0173] Diethyl2-([[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]methylene)malonate

[0174] Following the procedure described in Reference Example 1-2, thetitle compound was prepared from 1-(2-pyridinyl)-1H-pyrazol-5-amine anddiethyl ethoxymethylenemalonate (98% yield).

[0175] mp: 124-127° C. (recrystallized from ethyl acetate).

[0176] NMR (CDCl₃) δ: 1.34 (3H, t, J=7.0 Hz), 1.39 (3H, t, J=7.0 Hz),4.27 (2H, q, J=7.0 Hz), 4.38 (2H, q, J=7.0 Hz), 6.21 (1H, d, J=1.8 Hz),7.20-7.30 (1H, m), 7.58 (1H, d, J=1.8 Hz), 7.81-7.93 (1H, m), 7.99 (1H,d, J=8.4 Hz), 8.29 (1H, d, J=13.6 Hz), 8.53-8.60 (1H, m), hidden (1H).

[0177] Elementary Analysis: for C₁₆H₁₈N₄O₄

[0178] Calcd.: C, 58.17; H, 5.49; N, 16.96.

[0179] Found: C, 58.11; H, 5.41; N, 17.03.

Reference Example 1-5

[0180] Ethyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0181] A solution of ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(3.0 g, 0.01 mol) in phosphorous oxychloride (7.7 g, 0.05 mol) washeated and stirred at 100° C. for 1 hour. After the solution was allowedto cool to room temperature, the reaction solvent was evaporated underreduced pressure, and the residue water was added to iced water. Afterneutralization by the addition of an aqueous sodium hydroxide solution,organic matter was extracted with chloroform. The extract was washedwith saturated brine and water, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure.Purification of the residue by silica gel chromatography (ethyl acetate)gave the title compound (1.72 g, 54% yield).

[0182] mp: 121-123° C. (recrystallized from ethyl acetate).

[0183] NMR (CDCl₃) δ: 1.45 (3H, t, J=7.3 Hz), 2.90 (3H, s), 4.48 (2H, q,J=7.3 Hz), 7.26-7.34 (1H, m), 7.87-7.97 (1H, m), 8.33-8.41 (1H, m),8.67-8.73 (1H, m), 9.10 (1H, s).

[0184] Elementary Analysis: for C₁₅H₁₃N₄O₂Cl

[0185] Calcd.: C, 56.88; H, 4.14; N, 17.69.

[0186] Found: C, 56.89; H, 3.98; N, 17.79.

Reference Example 1-6

[0187]4-Chloro-N,3-dimethyl-N-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0188] A solution of4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid (2.0 g, 7.4 mmol) in phosphorous oxychloride (15 mL, 63 mmol) washeated and stirred at 100° C. for 3 hours. After the solution was cooledto room temperature, the solvent was evaporated under reduced pressure.The residue was dissolved in tetrahydrofuran (50 mL). To the solution, asolution of N-methylaniline (1.0 mL, 9.2 mmol) and triethylamine (5.2mL, 37 mmol) in tetrahydrofuran (10 mL) was added at 0° C. After themixture was stirred at room temperature for 1.5 hours, the reactionsolvent was evaporated under reduced pressure. Purification of theresidue thus obtained by silica gel chromatography(chloroform:methanol=50:1 to 20:1) gave the title compound (2.14 g, 76%yield).

[0189] mp: 154-155° C. (recrystallized from hexane/diethylether).

[0190] NMR (CDCl₃) δ: 2.79 (3H, s), 3.57 (3H, s), 7.11-7.27 (6H, m),7.85 (1H, td, J=7.3, 1.4 Hz), 8.22 (1H, d, J=8.4 Hz), 8.35 (1H, s),8.62-8.66 (1H, m).

[0191] Elementary Analysis: for C₂₀H₁₆N₅OCl

[0192] Calcd.: C, 63.58; H, 4.27; N, 18.54.

[0193] Found: C, 63.32; H, 4.36; N, 18.24.

Reference Example 1-7

[0194] 4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine

[0195] Following the procedure described in Reference Example 1-5, thetitle compound was prepared from4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine (59%yield).

[0196] mp: 124-125° C. (recrystallized from ethyl acetate).

[0197] NMR (CDCl₃) δ: 2.86 (3H, s), 7.50 (1H, d, J=5.3 Hz), 7.63-7.70(1H, m), 8.43-8.52 (1H, m), 8.63 (1H, d, J=5.3 Hz), 8.75-8.83 (2H, m).

[0198] Elementary Analysis: for C₁₂H₉N₄Cl

[0199] Calcd.: C, 58.91; H, 3.71; N, 22.90.

[0200] Found: C, 58.93; H, 3.83; N, 22.83.

Reference Example 1-8

[0201][4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone

[0202] A solution of4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid (2.0 g, 7.4 mmol) in phosphorous oxychloride (19 mL, 200 mmol) washeated and stirred at 100° C. for 1.5 hours. After the solution wascooled to room temperature, the solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (50 mL) andcooled to −78° C. To the solution, a solution of phenylmagnesium bromide(1M tetrahydrofuran solution, 30 mL, 30 mmol) was added dropwise at thesame temperature, and the mixture was stirred for 1 hour, and at roomtemperature further for 0.5 hour. The mixture was poured into an aqueoussaturated ammonium chloride solution and organic matter was extractedwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. Purification of the residue by silica gelchromatography (hexane:chloroform:ethyl acetate=2:1:1 to 1:1:1) gave thetitle compound (0.83 g, 38% yield).

[0203] mp: 177-178° C. (recrystallized from hexane/diethylether).

[0204] NMR (CDCl₃) δ: 2.89 (3H, s), 7.26-7.33 (1H, m), 7.47-7.55 (2H,m), 7.62-7.70 (1H, m), 7.84-7.97 (3H, m), 8.37 (1H, d, J=8.4 Hz), 8.63(1H, s), 8.69-8.72 (1H, m).

[0205] Elementary Analysis: for C₁₉H₁₃N₄OCl

[0206] Calcd.: C, 65.43; H, 3.76; N, 16.06.

[0207] Found: C, 65.20; H, 3.72; N, 15.95

Reference Example 1-9

[0208] 2-Hydrazinopyridine

[0209] The title compound was prepared from the following proceduredescribed in J. Med. Chem., vol.28, p.1394 (1985). A mixture of2-chloropyridine (200 mL, 2.1 mol) and hydrazine monohydrate (400 mL,8.2 mol) was heated under reflux for 20 hours. After the solution wascooled to room temperature, excess hydrazine hydrate was removed underreduced pressure, and the residue was added to water. After the solutionwas made basic by the addition of a sodium hydroxide solution, organicmatter was extracted with chloroform. The extract was washed withsaturated brine and water, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (157 g, 68% yield). The compound was used in the followingprocess, without further purification.

Reference Example 1-10

[0210] 2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0211] A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (68.2 g,0.34 mol) and 2-hydrazinopyridine (37.1 g, 0.34 mol) in ethanol (500 mL)was heated under reflux for 1 hour. After the solution was cooled toroom temperature, the resulting crude crystals were filtered. Thecrystals were washed with ethanol and air-dried to give the titlecompound (50.2 g, 51% yield).

[0212] mp: 190-193° C. (recrystallized from methanol).

[0213] NMR (DMSO-d₆) δ: 2.35 (3H, s), 6.15 (1H, s), 6.87-6.97 (1H, m),7.05-7.15 (1H, m), 7.46-7.56 (1H, m), 7.69 (1H, d, J=8.4 Hz), 7.73-7.82(1H, m), 7.92 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=8.1 Hz, 1.5 Hz),8.45-8.50 (1H, m), 12.25 (1H, br s).

Reference Example 1-11

[0214] 2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0215] A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine(5.23g, 30 mmol), o-iodobenzoic acid (8.93 g, 36 mmol), copper acetate(II) (0.654 g, 3.6 mmol), and potassium carbonate (4.98 g, 36 mmol) inN,N-dimethylformamide (30 mL) was heated under reflux for 1 hour underan argon atmosphere. After the solution was cooled to room temperature,the mixture was added to water. The solution was made weakly acidic bythe addition of acetic acid, and the resulting crude crystals werecollected by filtration. The crystals were washed with water and airdried to give the title compound (8.64 g, 98% yield).

Reference Example 1-12

[0216] 2-(2-Oxopropyl)-4H-3,1-benzoxazin-4-one

[0217] To a solution of anthranilic acid (290 g, 2.1 mol) in acetone(1000 mL), diketene (460 mL, 6.0 mol) was added dropwise at roomtemperature. The mixture was stirred at room temperature for 16 hours.The resulting crystals were collected by filtration, washed with acetoneand diethylether, and air dried (170 g). The crude crystals weresuspended in a mixture of acetic anhydride (320 mL, 3.4 mol) andtetrahydrofuran (1000 mL), and the mixture was heated and stirred at 80°C. for 12 hours. After the mixture was cooled to room temperature, thereaction solvents were evaporated under reduced pressure, and theresulting crude crystals were filtered. The crystals were washed withacetonitrile and air dried to give the title compound (244 g, 57%yield).

[0218] mp: 120-122° C. (recrystallized from acetonitrile).

Reference Example 1-13

[0219] 8-Methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0220] Following the procedure described in Reference Example 1-12, thetitle compound was prepared from 2-amino-3-methylbenzoic acid (88%yield).

[0221] mp: 150-152° C. (recrystallized from ethanol).

[0222] Elementary Analysis: for C₁₂H₁₁NO₃

[0223] Calcd.: C, 66.35; H, 5.10; N, 6.45.

[0224] Found: C, 66.36; H, 5.12; N, 6.38.

Reference Example 1-14

[0225] 8-Methoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0226] Following the procedure described in Reference Example 1-12, thetitle compound was prepared from 2-amino-3-methoxybenzoic acid (92%yield).

[0227] mp: 177-180° C. (recrystallized from methanol/ethyl acetate).

[0228] Elementary Analysis: for C₁₂H₁₁NO₄

[0229] Calcd.: C, 61.80; H, 4.75; N, 6.01.

[0230] Found: C, 61.81; H, 4.72; N, 6.01.

Reference Example 1-15

[0231] 6,7-Dimethoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0232] Following the procedure described in Reference Example 1-12, thetitle compound was prepared from 2-amino-4,5-dimethoxybenzoic acid (65%yield).

[0233] mp: 200-202° C. (recrystallized from acetonitrile).

[0234] Elementary Analysis: for C₁₃H₁₃NO₅

[0235] Calcd.: C, 59.31; H, 4,98; N, 5.32.

[0236] Found: C, 59.28; H, 4.91; N, 5.56.

Reference Example 1-16

[0237]4,5-Dimethoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0238] Following the procedure described in Reference Example 1-10, thetitle compound was prepared from6,7-dimethoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinopyridine (64% yield).

[0239] NMR (DMSO-d₆) δ: 2.24 (3H, s), 3.75 (3H, s), 3.86 (3H, s), 6.27(1H, s), 7.14 (1H, s), 7.26-7.33 (1H, m), 7.41 (1H, s), 7.83 (1H, d,J=8.0 Hz), 7.97 (1H, dt, J=1.8 Hz, 8.4Hz), 8.41-8.45 (1H, m), hidden(2H).

Reference Example 1-17

[0240] 6-(Methylsulfanyl)-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0241] Following the procedure described in Reference Example 1-12, thetitle compound was prepared from 2-amino-5-(methylsulfanyl)benzoic acid(68% yield).

[0242] mp: 137-140° C. (recrystallized from ethyl acetate/hexane).

[0243] Elementary Analysis: for C₁₂H₁₁NO₃S

[0244] Calcd.: C, 57.82; H, 4.45; N, 5.62.

[0245] Found: C, 57.80; H, 4.61; N, 5.48.

Reference Example 1-18

[0246]5-(Methylsulfanyl)-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0247] Following the procedure described in Reference Example 1-10, thetitle compound was prepared from6-(methylsulfanyl)-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinopyridine (67% yield).

[0248] NMR (DMSO-d₆) δ: 2.24 (3H, s), 2.47 (3H, s), 6.21 (1H, s), 7.31(1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4 Hz), 7.48 (1H, dd, J=2.2 Hz, 8.8 Hz),7.60 (1H, d, J=8.8 Hz), 7.81-7.86 (2H, m), 7.98 (1H, ddd, J=1.8 Hz, 7.4Hz, 8.4 Hz), 8.44 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 12.18 (1H, s),hidden (1H).

Reference Example 1-19

[0249] 6-Chloro-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0250] Following the procedure described in Reference Example 1-12, thetitle compound was prepared from 2-amino-5-chlorobenzoic acid (46%yield).

[0251] mp: 159-160° C. (recrystallized from acetonitrile).

[0252] Elementary Analysis: for C₁₁H₈ClNO₃

[0253] Calcd.: C, 57.82; H, 4.45; N, 5.62.

[0254] Found: C, 57.80; H, 4.61; N, 5.48.

Reference Example 1-20

[0255] 2-Amino-5-fluorobenzoic acid

[0256] A mixture of 5-fluoro-2-nitrotoluene (25.0 g, 161 mmol),potassium permanganate (102 g, 645 mmol) and water (500 mL) was heatedand stirred at 100° C. for 3 hours. The solution was cooled to roomtemperature, and insoluble matter derived from potassium permanganatewas removed by celite filtration. The filtrate was washed withdiethylether, made acidic by the addition of conc. hydrochloric acid,and organic matter was extracted with diethyl ether. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give5-fluoro-2-nitrobenzoic acid. To a solution of 5-fluoro-2-nitro benzoicacid thus obtained in ethanol (100 mL) was added 10% palladium-carbon(0.5 g, 50% hydrate), and the mixture was stirred at room temperatureunder hydrogen atmosphere for 4 hours. The solution was filtered toremove the catalyst, and the filtrate was concentrated under reducedpressure to give the title compound (6.25 g, 25% yield).

[0257] NMR (CDCl₃) δ: 5.94 (3H, br s), 6.64 (1H, dd, J=4.6 Hz, 9.0 Hz),7.04-7.15 (1H, m), 7.60 (1H, dd, J=3.0 Hz, 9.6 Hz).

Reference Example 1-21

[0258] 5-Fluoro-2-iodobenzoic acid

[0259] The title compound was prepared from the following proceduredescribed in Collection Czechoslov. Chem. Commun., vol.40, p.719 (1975).To an ice-cold mixture of 2-amino-5-fluorobenzoic acid (9.0 g, 58.0mmol) and conc. hydrochloric acid (50 mL) was added dropwise a solutionof sodium nitrite (4.42 g, 64.1 mmol) in water (10 mL). Subsequently, asolution of potassium iodide (14.5 g, 87.5 mmol) and conc. sulfuric acid(4 mL) in water (30 mL) was added at the same temperature, and themixture was heated to 100° C. and stirred for 2 hours. After thesolution was cooled to room temperature, the mixture was poured into anaqueous solution of sodium thiosulfate, and organic matter was extractedwith ethyl acetate. The extract was washed with saturated brine andwater, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give crude crystals. The crystals were collected byfiltration, washed with hexane/diethylether, and air dried to give thetitle compound (6.33 g, 41% yield).

[0260] NMR (CDCl₃) δ: 6.99 (1H, ddd, J=3.0 Hz, 5.4 Hz, 8.8 Hz), 7.76(1H, dd, J=3.0 Hz, 8.8 Hz), 8.02 (1H, dd, J=5.4 Hz, 8.8 Hz), hidden(1H).

Reference Example 1-22

[0261] 2-Hydrazino-3-methylpyridine

[0262] The title compound was prepared according to the proceduredescribed in U.S. Pat. No. 4,260,767 (1981). A mixture of2-bromo-3-methylpyridine (29.0 g, 169 mmol) and hydrazine monohydrate(60 mL, 1.24 mol) was heated and stirred at 100° C. for 4 hours. Themixture was ice cooled, and the resulting crude crystals were filtered.The crystals were washed with cold water and air dried, andrecrystallized from chloroform/hexane to give the title compound (12.5g, 60% yield).

[0263] NMR (DMSO-d₆) δ: 2.03 (3H, s), 4.10 (2H, br s), 6.53 (1H, dd,J=5.2 Hz, 7.4 Hz), 7.09 (1H, br s), 7.23 (1H, dd, J=1.0 Hz, 7.4 Hz),7.94 (1H, dd, J=1.0 Hz, 5.2 Hz).

Reference Example 1-23

[0264] 3-Hydrazinopyridine dihydrochloride

[0265] To a mixture of 3-aminopyridine (9.41 g, 100 mmol) and conc.hydrochloric acid (100 mL) was cooled to a temperature of lower than −5°C., a solution of sodium nitrite (7.20 g, 105 mmol) in water (60 mL) wasadded dropwise thereto. Subsequently, a solution of tin chloride (II)(56.9 g, 300 mmol) in conc. hydrochloric acid (50 mL) was added to thesolution so that the temperature of the solution does not exceed −5° C.,and the solution was stirred at a temperature of less than −5° C. for 3hours, and the resulting crystals were collected by filtration. Thecrystals were washed with diethylether/methanol and air dried to givethe title compound (15.6 g, 85% yield). The compound was used in thefollowing process without further purification.

Reference Example 1-24

[0266] 2-[[3-Methyl-1-(3-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0267] A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (10.2 g,50.0 mmol), 3-hydrazinopyridine dihydrochloride (9.10 g, 50.0 mmol) andsodium acetate (9.84 g, 120 mmol) in ethanol (100 mL) was heated underreflux for 1 hour. The solution was cooled to room temperature, and thereaction solvent was evaporated under reduced pressure. The residue waspoured into water, and organic matter was extracted with a mixed solventof chloroform/methanol. The extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was crystallized from ethylacetate/diethylether/hexane to give the title compound (10.1 g, 69%yield).

[0268] NMR (DMSO-d₆) δ: 2.27 (3H, s), 6.27 (1H, s), 6.77-6.84 (1H, m),6.91 (1H, d, J=8.2 Hz), 7.38 (1H, t, J=7.6 Hz), 7.45-7.52 (1H, m), 7.88(1H, d, J=7.6 Hz), 7.97 (1H, d, J=7.6 Hz), 8.50-8.53 (1H, m), 8.79 (1H,s), 9.94 (1H, br s), hidden (1H).

Reference Example 1-25

[0269] 2-Hydrazinopyrimidine

[0270] The title compound was prepared according to the proceduredescribed in Yakugaku Zasshi, vol.73, p.598 (1953). A mixture of2-chloropyrimidine (25.0 g, 218 mmol), potassium carbonate (25.0 g, 181mmol), and hydrazine monohydrate (50 mL, 1.01 mol) was heated andstirred at 100° C. for 20 minutes. The solution was ice cooled and theresulting crude crystals were collected by filtration. The crystals werewashed with cold water and air dried, and recrystallized from benzene togive the title compound (19.7 g, 82% yield).

[0271] NMR (DMSO-d₆) δ: 4.12 (2H, br s), 6.60 (1H, t, J=4.8 Hz), 8.10(1H, br s), 8.31 (2H, d, J=4.8 Hz).

Reference Example 1-26

[0272] Ethyl 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate

[0273] A solution of ethyl 2-(ethoxymethylene)-2-cyanacetate (33.8 g,200 mmol) and 2-hydrazinopyridine (21.8 g, 200 mmol) in ethanol (100 mL)was heated under reflux for 20 minutes. The solution was cooled to roomtemperature, and the resulting crystals were collected by filtration.The crystals were washed with ethanol and air dried to give the titlecompound (33.8g, 73% yield).

[0274] mp: 103-104° C. (recrystallized from ethyl acetate).

[0275] NMR (CDCl₃) δ: 1.37 (3H, t, J=7.0 Hz), 4.31 (2H, q, J=7.0 Hz),7.12-7.18 (1H, m), 7.48 (2H, br s), 7.76 (1H, s), 7.77-7.87 (1H, m),7.95 (1H, d, J=8.4 Hz), 8.35-8.38 (1H, m).

Reference Example 1-27

[0276] 1-(2-Pyridinyl)-1H-pyrazol-5-ylamine

[0277] A suspension of ethyl5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate (27.9 g, 120 mmol) in4N sodium hydroxide (300 mL) solution was heated under reflux for 1hour. The mixture was cooled to room temperature, neutralized with conc.hydrochloric acid, and made acidic with acetic acid. The resultingcrystals were collected by filtration, washed with ethanol, and airdried. The crystals was subjected to heat at a temperature of 200° C.,and then washed with diethylether to give the title compound (6.02 g,31% yield).

[0278] NMR (CDCl₃) δ: 5.51 (1H, d, J=1.8 Hz), 5.95 (2H, br s), 7.07-7.13(1H, m), 7.42 (1H, d, J=1.8 Hz), 7.75-7.84 (1H, m), 7.98 (1H, d, J=8.4Hz), 8.33 (1H, dd, J=1.6 Hz, 4.6 Hz).

Reference Example 1-28

[0279] 2-[[1-(2-Pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0280] Following the procedure described in Reference Example 1-11, thetitle compound was prepared from o-iodobenzoic acid and1-(2-pyridinyl)-1H-pyrazol-5-ylamine (90% yield).

[0281] mp: 216-218° C. (recrystallized from ethanol).

[0282] NMR (DMSO-d₆) δ: 6.40 (1H, d, J=2.2 Hz), 6.90-6.98 (1H, m), 7.37(1H, ddd, J=1.2Hz, 5.0 Hz, 7.2 Hz), 7.48-7.57 (1H, m), 7.61 (1H, dd,J=1.0 Hz, 8.4 Hz), 7.69 (1H, d, J=2.2 Hz), 7.88-8.08 (3H, m), 8.49 (1H,dd, J=1.0 Hz, 5.0 Hz), 12.20 (1H, br s), hidden (1H).

[0283] Elementary Analysis: for C₁₅H₁₂N₄O₂

[0284] Calcd.: C, 64.28; H, 4.32; N, 19.99.

[0285] Found: C, 64.44; H, 4.26; N, 20.11.

EXAMPLE 1-1

[0286] Ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0287] A solution of diethyl2-([[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]methylene)malonate(2.0 g, 5.8 mmol) in polyphosphoric acid (10 g) was heated and stirredat 100° C. for 2 hours. The solution was cooled to room temperature, andiced water was added thereto. The solution was neutralized by theaddition of an aqueous sodium hydroxide solution, and organic matter wasextracted with 10% methanol/chloroform. The extract was washed withsaturated brine and water, dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. Purification of theresidue by silica gel column chromatography (chloroform) gave the titlecompound (0.98 g, 57% yield).

[0288] mp: 166-169° C. (recrystallized from ethyl acetate).

[0289] NMR (CDCl₃) δ: 1.46 (3H, t, J=7.3 Hz), 2.79 (3H, s), 4.49 (2H, q,J=7.3 Hz), 7.20-7.33 (1H, m), 7.83-7.95 (1H, m), 8.36 (1H, d, J=8.4 Hz),8.67 (1H, d, J=4.0 Hz), 8.97 (1H, s), 12.25 (1H, s).

[0290] Elementary Analysis: for C₁₅H₁₄N₄O₃

[0291] Calcd.: C, 60.40; H, 4.73; N, 18.78.

[0292] Found: C, 60.28; H, 4.54; N, 18.79.

EXAMPLE 1-2

[0293]4-Hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

[0294] A suspension of ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(2.0 g, 6.7 mmol) in 6N hydrochloric acid solution (10 mL) was heatedand stirred at 100° C. for 1 hour. The solution was cooled to roomtemperature, made weakly acidic by the addition of an aqueous sodiumhydroxide solution, and the resulting precipitate was collected byfiltration. The crude crystals thus obtained were washed with water anddried to give the title compound (0.6 g, 33% yield).

[0295] mp: 248-251° C.

[0296] NMR (DMSO-d₆) δ: 2.60 (3H, s), 3.32 (1H, br s), 7.44 (1H, t,J=6.6 Hz), 7.90 (1H, d, J=8.4 Hz), 8.08 (1H, t, J=6.6 Hz), 8.48-8.63(2H, m), hidden (1H).

EXAMPLE 1-3

[0297] 3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0298] A suspension of4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid (2.0 g, 6.7 mmol) in phosphoric acid (10 mL) was heated and stirredat 180° C. for 12 hours. The reaction solution was cooled to roomtemperature, neutralized by the addition of an aqueous sodium hydroxidesolution, and organic matter was extracted with chloroform. The extractwas washed with saturated brine and water, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. Purification of the residue by silica gel columnchromatography (chloroform:methanol=95:5) gave the title compound (230mg, 15% yield).

[0299] mp: 241-243° C. (recrystallized from ethanol).

[0300] NMR (CDCl₃) δ: 2.70 (3H, s), 6.21 (1H, d, J=7.3 Hz), 7.17-7.25(1H, m), 7.49 (1H, d, J=7.3 Hz), 7.83-8.02 (2H, m), 8.40-8.45 (1H, m),11.56 (1H, br s).

EXAMPLE 1-4

[0301][4-Hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone

[0302] A mixture of methanesulfonic acid (30 mL) and phosphoruspentoxide (6 g) was heated at 100° C. The mixture was stirred thoroughlyat the temperature, with gradual addition of powdery ethyl2-benzoyl-3-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-propenoate(3.0 g, 8.0 mmol). The mixture was further heated and stirred at thetemperature for 30 minutes. The solution was cooled to room temperature,iced water was added thereto. The solution was neutralized by theaddition of an aqueous sodium hydroxide solution, and organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. Purification of the residue bybasic silica gel column chromatography (chloroform) gave the titlecompound (880 mg, 34% yield).

[0303] mp: 224-226° C. (recrystallized from ethyl acetate/methanol).

[0304] NMR (CDCl₃) δ: 2.83 (3H, s), 7.20-8.00 (10H, m), 8.82 (1H, br s).

[0305] Elementary Analysis: for C₁₉H₁₄N₄O₂

[0306] Calcd.: C, 69.08; H, 4.27; N, 16.96.

[0307] Found: C, 68.82; H, 4.31; N, 17.13.

EXAMPLE 1-5

[0308][1-(6-Ethoxy-2-pyridinyl)-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone

[0309] Following the procedure described in Reference Example 1-1,3-methyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazol-5-amine was prepared fromamino crotonitrile and 6-ethoxy-2-hydrazinopyridine. Following theprocedure described in Reference Example 1-2, the compound was subjectedto a reaction with ethyl 2-benzoyl-3-ethoxy-2-propenoate to give ethyl2-benzoyl-3-[[3-methyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-propenoate.The compound was treated following the method described in Example 1-4to give the title compound (35% cyclization yield).

[0310] mp: 160-162° C. (recrystallized from ethyl acetate).

[0311] NMR (CDCl₃) δ: 1.45 (3H, t, J=7.0 Hz), 2.78 (3H, s), 4.44 (2H, q,J=7.0 Hz), 6.71 (1H, d, J=8.1 Hz), 7.45-7.85 (8H, m), 8.73 (1H, br s).

EXAMPLE 1-6

[0312] Ethyl4-hydroxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0313] Following the procedure described in Example 1-1, the titlecompound was prepared from diethyl2-([[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]methylene)malonate (41%yield).

[0314] mp: 195-197° C. (recrystallized from chloroform/methanol).

[0315] NMR (CDCl₃) δ: 1.46 (3H, t, J=7.0 Hz), 4.50 (2H, q, J=7.0 Hz),7.25-7.35 (1H, m), 7.87-7.98 (1H, m), 8.31 (1H, d, J=8.1 Hz), 8.40 (1H,s), 8.68 (1H, br s), 9.03 (1H, s), 12.25 (1H, br s).

[0316] Elementary Analysis: for C₁₄H₁₂N₄O₃

[0317] Calcd.: C, 59.15; H, 4.25; N, 19.71.

[0318] Found: C, 59.00; H, 4.30; N, 19.80.

EXAMPLE 1-7

[0319] 1-(2-Pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0320] Following the procedure described in Example 1-3, the titlecompound was prepared from ethyl4-hydroxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (99%yield).

[0321] mp: 192-194° C. (recrystallized from ethyl acetate/methanol).

[0322] NMR (CDCl₃) δ: 6.28 (1H, d, J=7.3 Hz), 7.23-7.30 (1H, m), 7.53(1H, d, J=7.7 Hz), 7.88-7.99 (1H, m), 8.05 (1H, br, d, J=8.4 Hz), 8.26(1H, s), 8.43-8.48 (1H, m), 11.56 (1H, br s).

[0323] Elementary Analysis: for C₁₁H₈N₄O.H₂O

[0324] Calcd.: C, 57.39; H, 4.38; N, 24.34.

[0325] Found: C, 57.51; H, 4.24; N, 24.29.

EXAMPLE 1-8

[0326]N-Cyclohexyl-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0327] A mixed solution of ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(1.5 g, 5.0 mmol) and cyclohexylamine (2.2 g, 22 mmol) in xylene (5.0mL) and dimethylsulfonamide (5.0 mL) was stirred at 130° C. for 28hours. The solution was cooled to room temperature and water was addedthereto. Subsequently, organic matter was extracted with ethyl acetate.The extract was washed with saturated brine and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.Purification of the residue by silica gel column chromatography(chloroform:methanol=50:1 to 20:1) gave crude crystals. The crudecrystals were recrystallized from ethyl acetate/ethanol to give thetitle compound (0.17 g, 10% yield).

[0328] mp: >300° C. (recrystallized from ethyl acetate/ethanol).

[0329] NMR (CDCl₃) δ: 1.22-1.46 (4H, m), 1.52-1.80 (4H, m), 1.94-2.04(2H, m), 2.73 (3H, s), 3.98 (1H, br), 7.22-7.28 (1H, m), 7.87-8.02 (2H,m), 8.45 (1H, d, J=4.4 Hz), 8.72 (1H, d, J=5.8 Hz), 9.99 (1H, d, J=8.0Hz), 11.84 (1H, br s).

[0330] Elementary Analysis: for C₁₉H₂₁N₅O₂

[0331] Calcd.: C, 64.94; H, 6.02; N, 19.93.

[0332] Found: C, 64.82; H, 6.18; N, 19.69.

EXAMPLE 1-9

[0333]N-Benzyl-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0334] A mixture of ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(2.0 g, 6.7 mmol) and benzylamine (8.0 mL, 73 mmol) was stirred at 180°C. for 16 hours under an argon atmosphere. The mixture was cooled toroom temperature, ethyl acetate was added thereto. The resulting crudecrystals were collected by filtration, and washed with ethyl acetate.The crude crystals thus obtained were purified by silica gel columnchromatography (chloroform:methanol=20:1 to 5:1), and recrystallizedfrom ethanol to give the title compound (1.5 g, 60% yield).

[0335] mp: >300° C. (recrystallized from ethanol).

[0336] NMR (CDCl₃/CF₃CO₂D, 50:1) δ: 2.80 (3H, s), 4.66 (2H, s),7.33-7.44 (6H, m), 8.04-8.07 (2H, m), 8.48-8.51 (1H, m), 9.11 (1H, s),hidden (2H).

[0337] Elementary Analysis: for C₂₀H₁₇N₅O₂

[0338] Calcd.: C, 66.84; H, 4.77; N, 19.49.

[0339] Found: C, 66.77; H, 4.72; N, 19.38.

EXAMPLE 1-10

[0340][4-Hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl](1-piperidinyl)methanone

[0341] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand piperidine (32% yield).

[0342] mp: 264-266° C. (recrystallized from ethyl acetate/ethanol).

[0343] NMR (CDCl₃) δ: 1.65 (6H, br), 2.66 (3H, s), 3.39 (2H, br), 3.72(2H, br), 7.18-7.24 (1H, m), 7.74 (1H, d, J=5.2 Hz), 7.83-7.98 (2H, m),8.41 (1H, d, J=5.2 Hz), 11.62 (1H, br).

[0344] Elementary Analysis: for C₁₈H₁₉N₅O₂

[0345] Calcd.: C, 64.08; H, 5.68; N, 20.76.

[0346] Found: C, 64.08; H, 5.93; N, 20.79

EXAMPLE 1-11

[0347]4-Hydroxy-3-methyl-N-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0348] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand aniline (16% yield).

[0349] mp: >300° C. (recrystallized from ethanol).

[0350] NMR (CDCl₃/CF₃CO₂D, 50:1) δ: 2.83 (3H, s), 7.26-7.33 (1H, m),7.40-7.47 (3H, m), 7.60 (2H, d, J=8.2 Hz), 8.06-8.10 (2H, m), 8.53 (1H,d, J=5.2 Hz), 9.27 (1H, s), hidden (2H).

[0351] Elementary Analysis: for C₁₉H₁₅N₅O₂

[0352] Calcd.: C, 66.08; H, 4.38; N, 20.28.

[0353] Found: C, 65.81; H, 4.37; N, 20.31

EXAMPLE 1-12

[0354]N-(2-Fluorophenyl)-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0355] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 2-fluoroaniline (23% yield).

[0356] mp: >300° C. (recrystallized from ethanol).

[0357] NMR (CDCl₃/CF₃CO₂D, 50:1) δ: 2.79 (3H, s), 7.13-7.29 (3H, m),7.37-7.43 (1H, m), 7.86-7.95 (1H, m), 8.01-8.10 (2H, m), 8.53 (1H, d,J=5.4 Hz), 9.19 (1H, s), hidden (2H).

[0358] Elementary Analysis: for C₁₉H₁₄N₅O₂F

[0359] Calcd.: C, 62.81; H, 3.88; N, 19.27.

[0360] Found: C, 62.62; H, 4.08; N, 19.31.

EXAMPLE 1-13

[0361]N-(3-Fluorophenyl)-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0362] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 3-fluoroaniline (19% yield).

[0363] mp: >300° C. (recrystallized from ethanol).

[0364] NMR (CDCl₃) δ: 2.83 (3H s), 6.96-7.04 (1H, m), 7.31-7.54 (4H, m),8.10-8.16 (2H, m), 8.54 (1H, dd, J=5.3, 1.6 Hz), 9.25 (1H, s), 11.18(2H, br s).

[0365] Elementary Analysis: for C₁₉H₁₄N₅O₂F

[0366] Calcd.: C, 62.81; H, 3.88; N, 19.27.

[0367] Found: C, 62.62; H, 4.08; N, 19.31.

EXAMPLE 1-14

[0368]N-(4-Fluorophenyl)-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0369] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 4-fluoroaniline (14% yield).

[0370] mp: >300° C. (recrystallized from ethanol).

[0371] NMR (CDCl₃/CF₃CO₂D, 50:1) δ: 2.81 (3H, s), 7.07-7.16 (2H, m),7.36-7.45 (1H, m), 7.56-7.63 (2H, m), 8.06-8.09 (2H, m), 8.52-8.55 (1H,m), 9.24 (1H, s), hidden (2H).

[0372] Elementary Analysis: for C₁₉H₁₄N₅O₂F

[0373] Calcd.: C, 62.81; H, 3.88; N, 19.27.

[0374] Found: C, 62.88; H, 3.87; N, 19.31.

EXAMPLE 1-15

[0375]N-(3,4-Difluorophenyl)-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0376] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 3,4-difluoroaniline (7% yield).

[0377] mp: >300° C. (recrystallized from ethanol).

[0378] NMR (CDCl₃/CF₃CO₂D, 10:1) δ: 2.84 (3H, s), 7.14-7.28 (2H, m),

[0379] 7.44-7.51 (1H, m), 7.57-7.67 (1H, m), 8.12-8.14 (2H, m),8.53-8.55 (1H, m), 9.23 (1H, s), 10.21 (1H, br s), hidden (1H).

[0380] Elementary Analysis: for C₁₉H₁₃N₅O₂F₂

[0381] Calcd.: C, 59.84; H, 3.44; N, 18.36.

[0382] Found: C, 59.66; H, 3.43; N, 18.26.

EXAMPLE 1-16

[0383]N-[(3,5-Bis(trifluoromethyl)phenyl]-4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0384] Following the procedure described in Example 1-9, the titlecompound was prepared from ethyl4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylateand 3,5-bis(trifluoromethyl)aniline (49% yield).

[0385] mp: 283-285° C. (recrystallized from ethanol).

[0386] NMR (CDCl₃) δ: 2.77 (3H, s), 7.23-7.30 (1H, m), 7.57 (1H, s),7.88-8.03 (2H, m), 8.27 (2H, s), 8.44-8.47 (1H, m), 8.79 (1H, d, J=6.2Hz), 12.16 (1H, br), 12.80 (1H, br s).

[0387] Elementary Analysis: for C₂₁H₁₃N₅O₂F₆.H₂O

[0388] Calcd.: C, 50.51; H, 3.03; N, 14.02.

[0389] Found: C, 50.28; H, 2.86; N, 14.05.

EXAMPLE 1-17

[0390]4-(Benzyloxy)-N,3-dimethyl-N-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0391] To a solution of benzyl alcohol (0.40 g, 3.7 mmol) inN,N-dimethylformamide (10 mL), sodium hydride (0.16 g, 40 mmol, 60% oil)was added at room temperature, and the resulting mixture was stirred atthe same temperature for 30 minutes. To the solution, a solution of4-chloro-N,3-dimethyl-N-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide(1.0 g, 2.8 mmol) in N,N-dimethylformamide (10 mL) solution was added atroom temperature, and stirred at 100° C. for 11.5 hours. The mixture wasconcentrated under reduced pressure, and the residue was poured intowater. Organic matter was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. Purification of theresulting residue by silica gel chromatography (hexane:chloroform:ethylacetate=2:1:1 to 1:1:1 to 1:2:2) gave the title compound (0.99 g, 80%yield).

[0392] mp: 92-93° C. (crystallized from hexane/chloroform/ethylacetate).

[0393] NMR (CDCl₃) δ: 2.53 (3H, s), 3.56 (3H, s), 5.43 (2H, s),7.01-7.23 (5H, m), 7.27-7.51 (6H, m), 7.83 (1H, td, J=7.7, 2.2 Hz), 8.28(1H, d, J=8.4 Hz), 8.39 (1H, s), 8.62 (1H, d, J=3.8 Hz).

[0394] Elementary Analysis: for C₂₇H₂₃N₅O₂.1.6CHCl₃

[0395] Calcd.: C, 53.63; H, 3.87; N, 10.93.

[0396] Found: C, 53.42; H, 3.77; N, 10.92.

EXAMPLE 1-18

[0397] 3,6-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0398] A mixture of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (1.8 g,10 mmol) and polyphosphoric acid (4.2 g) was heated at 130° C. Themixture was stirred thoroughly at the same temperature, while ethylacetoacetate (1.3 mL, 10 mmol) was added dropwise thereto, and theresulting mixture was stirred at the same temperature for 1 hour. Themixture was cooled to room temperature, iced water was added thereto.The mixture was neutralized with an aqueous sodium hydroxide solution,and organic matter was extracted with chloroform. The extract was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue thus obtainedwas purified by silica gel column chromatography(chloroform:methanol=50:1 to 20:1), and recrystallized from ethylacetate to give the title compound (0.72 g, 30% yield).

[0399] mp: 175-176° C. (recrystallized from ethyl acetate).

[0400] NMR (CDCl₃) δ: 2.43 (3H, s), 2.68 (3H, s), 6.03 (1H, d, J=1.0Hz), 7.17-7.23 (1H, m), 7.88 (1H, td, J=8.5, 2.0 Hz), 7.98 (1H, d, J=8.5Hz), 8.40-8.43 (1H, m), 11.13 (1H, br).

[0401] Elementary Analysis: for C₁₃H₁₂N₄O.1.5H₂O

[0402] Calcd.: C, 58.42; H, 5.66; N, 20.96.

[0403] Found: C, 58.97; H, 5.63; N, 21.11.

EXAMPLE 1-19

[0404] 3,5,6-Trimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0405] Following the procedure described in Example 1-18, a mixturecontaining the title compound as the main component was prepared from3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine and ethyl2-methylacetoacetate (16% yield).

[0406] mp: 187-188° C. (recrystallized from ethyl acetate).

[0407] NMR (CDCl₃) δ: 2.08 (3H, s), 2.44 (3H, s), 2.70 (3H, s),7.14-7.21 (1H, m), 7.82-7.98 (2H, m), 8.39-8.43 (1H, m), 10.98 (1H, br).

EXAMPLE 1-20

[0408]5-Benzyl-3,6-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0409] Following the procedure described in Example 1-18, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl 2-benzylacetoacetate (15% yield).

[0410] mp: 181-182° C. (recrystallized from ethyl acetate).

[0411] NMR (CDCl₃) δ: 2.41 (3H, s), 2.72 (3H, s), 4.00 (2H, s),7.14-7.30 (6H, m), 7.86 (1H, td, J=7.9, 1.8 Hz), 7.97 (1H, d, J=8.4 Hz),8.40 (1H, d, J=4.0 Hz), 11.03 (1H, br).

[0412] Elementary Analysis: for C₂₀H₁₈N₄O

[0413] Calcd.: C, 72.71; H, 5.49; N, 16.96.

[0414] Found: C, 72.67; H, 5.49; N, 17.02.

EXAMPLE 1-21

[0415] 6-Benzyl-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0416] Following the procedure described in Example 1-18, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl 3-oxo-4-phenylbutanoate (14% yield).

[0417] mp: 168-169° C. (recrystallized from ethyl acetate).

[0418] NMR (CDCl₃) δ: 2.67 (3H, s), 4.02 (2H, s), 6.14 (1H, t, J=0.8Hz), 7.08-7.14 (1H, m), 7.32-7.47 (5H, m), 7.77-7.92 (2H, m), 8.09-8.13(1H, m), 11.11 (1H, br).

[0419] Elementary Analysis: for C₁₉H₁₆N₄O

[0420] Calcd.: C, 72.14; H, 5.10; N, 17.71.

[0421] Found: C, 71.91; H, 5.16; N, 17.53.

EXAMPLE 1-22

[0422] 3-Methyl-6-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

[0423] Following the procedure described in Example 1-18, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl benzoylacetate (32% yield).

[0424] mp: 198-199° C. (recrystallized from ethyl acetate).

[0425] NMR (CDCl₃) δ: 2.73 (3H, s), 6.52 (1H, d, J=1.8 Hz), 7.21 (1H, t,J=6.2 Hz), 7.54-7.58 (3H, m), 7.69-7.74 (2H, m), 7.86-7.95 (1H, m), 8.02(1H, d, J=8.4 Hz), 8.43 (1H, d, J=5.0 Hz), 11.73 (1H, br).

[0426] Elementary Analysis: for C₁₈H₁₄N₄O.H₂O

[0427] Calcd.: C, 67.49; H, 5.03; N, 17.49.

[0428] Found: C, 67.83; H, 5.18; N, 17.69.

EXAMPLE 1-23

[0429] 3,4-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-6-ol

[0430] A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (5.1 g,29 mmol) and ethyl acetoacetate (3.8 g, 30 mmol) in acetic acid (14 mL)was stirred at 100° C. for 4 hours. The solution was cooled to roomtemperature and ethyl acetate was added thereto. The resulting crudecrystals were collected by filtration, and recrystallized from ethanolto give the title compound (4.4 g, 62% yield).

[0431] mp: 254-255° C. (recrystallized from ethanol).

[0432] NMR (CDCl₃) δ: 2.46 (3H, s), 2.56 (3H, s), 6.13 (1H, s),7.15-7.22 (1H, m), 7.80-7.95 (2H, m), 8.39 (1H, d, J=4.8 Hz), 11.52 (1H,br).

[0433] Elementary Analysis: for C₁₃H₁₂N₄O

[0434] Calcd.: C, 64.99; H, 5.03; N, 23.32.

[0435] Found: C, 65.06; H, 5.15; N, 23.24.

EXAMPLE 1-24

[0436] 3,4,5-Trimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-6-ol

[0437] Following the procedure described in Example 1-19, the titlecompound as the by-product was prepared from3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine and ethyl2-methylacetoacetate (7% yield).

[0438] mp: 226-228° C. (recrystallized from ethyl acetate).

[0439] NMR (CDCl₃) δ: 2.16 (3H, s), 2.46 (3H, s), 2.59 (3H, s),7.13-7.20 (1H, m), 7.79-7.95 (2H, m), 8.41-8.43 (1H, m), 11.54 (1H, br).

[0440] Elementary Analysis: for C₁₄H₁₄N₄O

[0441] Calcd.: C, 66.13; H, 5.55; N, 22.03.

[0442] Found: C, 66.11; H, 5.35; N, 21.94.

EXAMPLE 1-25

[0443]5-Benzyl-3,4-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-6-ol

[0444] Following the procedure described in Example 1-23, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl 2-benzylacetoacetate (24% yield).

[0445] mp: 208-209° C. (recrystallized from ethyl acetate).

[0446] NMR (CDCl₃) δ: 2.46 (3H, s), 2.57 (3H, s), 4.07 (2H, s),7.15-7.30 (6H, m), 7.84 (1H, td, J=8.4, 1.8 Hz), 7.92 (1H, d, J=8.4 Hz),8.40 (1H, d, J=5.0 Hz), 11.60 (1H, br).

[0447] Elementary Analysis: for C₂₀H₁₈N₄O

[0448] Calcd.: C, 72.71; H, 5.49; N, 16.96.

[0449] Found: C, 72.83; H, 5.34; N, 16.90.

EXAMPLE 1-26

[0450] 4-Benzyl-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-6-ol

[0451] Following the procedure described in Example 1-23, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl 3-oxo-4-phenylbutanoate (37% yield).

[0452] mp: 222-224° C. (recrystallized from ethyl acetate).

[0453] NMR (CDCl₃) δ: 2.41 (3H, s), 4.14 (2H, s), 7.17-7.37 (7H, m),7.80-7.91 (2H, m), 8.39-8.42 (1H, m), 11.65 (1H, br)

[0454] Elementary Analysis: for C₁₉H₁₆N₄).

[0455] Calcd.: C, 72.14; H, 5.10; N, 17.71.

[0456] Found: C, 72.29; H, 4.93; N, 17.86.

EXAMPLE 1-27

[0457] 3-Methyl-4-phenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-6-ol

[0458] Following the procedure described in Example 1-23, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl benzoylacetate (13% yield).

[0459] mp: 195-196° C (recrystallized from ethanol).

[0460] NMR (CDCl₃) δ: 2.06 (3H, s), 6.26 (1H, s), 7.18-7.51 (6H, m),7.87 (1H, td, J=8.4, 2.0 Hz), 7.96 (1H, d, J=8.4 Hz), 8.43 (1H, d, J=4.8Hz), 11.78 (1H, br).

[0461] Elementary Analysis: for C₁₈H₁₄N₄O

[0462] Calcd.: C, 71.51; H, 4.67; N, 18.53.

[0463] Found: C, 71.55; H, 4.70; N, 18.36.

EXAMPLE 1-28

[0464]1-Methyl-3-(2-pyridinyl)-3,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]pyridin-5-ol

[0465] Following the procedure described in Example 1-23, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl 2-oxocyclopentanecarboxylate (17% yield).

[0466] mp: 255-256° C. (recrystallized from ethyl acetate).

[0467] NMR (CDCl₃) δ: 2.15-2.27 (2H, m), 2.50 (3H, s), 2.88 (2H, t,J=7.6 Hz), 3.12 (2H, t, J=8.1 Hz), 7.14-7.21 (1H, m), 7.79-7.95 (2H, m),8.39-8.43 (1H, m), 11.51 (1H, br).

[0468] Elementary Analysis: for C₁₅H₁₄N₄O

[0469] Calcd.: C, 67.65; H, 5.30; N, 21.04.

[0470] Found: C, 67.69; H, 5.31; N, 20.93.

EXAMPLE 1-29

[0471]1-Methyl-3-(2-pyridinyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-5-ol

[0472] Following the procedure described in Example 1-18, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand ethyl 2-cyclohexanonecarboxylate (19% yield).

[0473] mp: 248-249° C. (recrystallized from ethyl acetate).

[0474] NMR (CDCl₃) δ: 1.82 (4H, br), 2.56 (3H, s), 2.58 (2H, br), 2.90(2H, br), 7.13-7.19 (1H, m), 7.78-7.94 (2H, m), 8.40 (1H, dd, J=5.8, 0.8Hz), 11.47 (1H, br).

[0475] Elementary Analysis: for C₁₆H₁₆N₄O

[0476] Calcd.: C, 68.55; H, 5.75; N, 19.99.

[0477] Found: C, 68.42; H, 5.70; N, 19.99.

EXAMPLE 1-30

[0478]1-Methyl-3-(2-pyridinyl)-3,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridin-5-ol

[0479] Following the procedure described in Example 1-18, the titlecompound was prepared from 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amineand methyl 2-oxocycloheptanecarboxylate (8% yield).

[0480] mp: 243-244° C. (recrystallized from ethyl acetate/hexane).

[0481] NMR (CDCl₃) δ: 1.59 (2H, br), 1.65-1.73 (2H, m), 1.86-1.96 (2H,m), 2.58 (3H, s), 2.89-2.95 (2H, m), 2.99-3.05 (2H, m), 7.13-7.20 (1H,m), 7.79-7.95 (2H, m), 8.40-8.43 (1H, m), 11.58 (1H, br).

[0482] Elementary Analysis: for C₁₇H₁₈N₄O

[0483] Calcd.: C, 69.37; H, 6.16; N, 19.03.

[0484] Found: C, 69.36; H, 6.18; N, 19.15.

EXAMPLE 1-31

[0485] Ethyl4-amino-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0486] A solution of ethyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(1.0 g, 3.2 mmol) and sodium azide (0.23 g, 3.5 mmol) inN,N-dimethylformamide (5 mL) was heated and stirred at 100° C. for 30minutes. The solution was cooled to room temperature, and poured intowater, and the resulting solution was made basic by the addition of anaqueous sodium hydroxide solution, and organic matter was extracted withchloroform. The extract was washed with saturated brine and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give ethyl4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.To a solution of the ethyl4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylatein ethanol (150 mL) was added 10% palladium-carbon (1.2 g, 50% hydrate),and the mixture was stirred at room temperature for 1 hour underhydrogen atmosphere. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. Purification of theresidue by silica gel column chromatography (basic silica gel, ethylacetate:methanol=93:7) gave the title compound (900 mg, 96% yield).

[0487] mp: 147-149° C. (recrystallized from ethyl acetate/hexane).

[0488] NMR (CDCl₃) δ: 1.41 (3H, t, J=7.3 Hz), 2.80 (3H, s), 4.38 (2H, q,J=7.3 Hz), 7.19-7.30 (1H, m), 7.81-7.93 (1H, m), 8.41 (1H, d, J=8.1 Hz),8.60-8.70 (1H m), 8.96 (1H s), hidden (2H).

[0489] Elementary Analysis: for C₁₅H₁₅N₅O₂.0.3H₂O

[0490] Calcd.: C, 59.52; H, 5.19; N, 23.13.

[0491] Found: C, 59.40; H, 5.16; N, 23.30.

EXAMPLE 1-32

[0492] 4-(Benzyloxy)-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine

[0493] Following the procedure described in Example 1-17, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine and benzylalcohol (54% yield).

[0494] mp: 108-110° C. (crystallized from hexane/diethylether).

[0495] NMR (CDCl₃) δ: 2.77 (3H, s), 5.31 (2H, s), 6.65 (1H, d, J=5.6Hz), 7.16-7.23 (1H, m), 7.37-7.51 (5H, m), 7.81-7.90 (1H, m), 8.42 (1H,dd, J=8.2, 0.8 Hz), 8.48 (1H, d, J=5.6 Hz), 8.64-8.67 (1H, m).

[0496] Elementary Analysis: for C₁₉H₁₆N₄O

[0497] Calcd.: C, 72.14; H, 5.10; N, 17.71.

[0498] Found: C, 72.11; H, 5.15; N, 17.80.

EXAMPLE 1-33

[0499]4-Hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone

[0500] A solution of[4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone(0.51 g, 1.5 mmol) and 6N hydrochloric acid (5.0 mL) in methanol (10 mL)was heated under reflux for 14 hours. The solution was cooled to roomtemperature, neutralized by the addition of a 1N sodium hydroxidesolution, and organic matter was extracted with chloroform. The extractwas washed with saturated brine and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate/methanol to give the title compound(0.36g, 75% yield).

[0501] NMR (CDCl₃) δ: 2.83 (3H, s), 7.20-8.00 (10H, m), 8.82 (1H, br s).

[0502] Chemical structures of the compounds obtained in Examples 1-1 to1-33 are summarized in the following Table 1 and Table 2. TABLE 1

Example Number R³ R¹ X Y Z 1-1  2-Py Me OH CO₂Et H 1-2  2-Py Me OH CO₂HH 1-3  2-Py Me OH H H 1-4  2-Py Me OH PhCO H 1-5  6-EtO-2-Py Me OH PhCOH 1-6  2-Py H OH CO₂Et H 1-7  2-Py H OH H H 1-8  2-Py Me OHcyclohexyl-NHCO H 1-9  2-Py Me OH PhCH₂NHCO H 1-10 2-Py Me OH1-piperidinyl-CO H 1-11 2-Py Me OH PhNHCO H 1-12 2-Py Me OH 2-F-PhNHCO H1-13 2-Py Me OH 3-F-PhNHCO H 1-14 2-Py Me OH 4-F-PhNHCO H 1-15 2-Py MeOH 3,4-F-PhNHCO H 1-16 2-Py Me OH 3,5-CF₃-PhNHCO H 1-17 2-Py Me PhCH₂OPhNMeCO H 1-18 2-Py Me OH H Me 1-19 2-Py Me OH Me Me 1-20 2-Py Me OHPhCH₂ Me 1-21 2-Py Me OH H PhCH₂ 1-22 2-Py Me OH H Ph 1-23 2-Py Me Me HOH 1-24 2-Py Me Me Me OH 1-25 2-Py Me Me PhCH₂ OH 1-26 2-Py Me PhCH₂ HOH 1-27 2-Py Me Ph H OH 1-31 2-Py Me NH₂ COOEt H 1-32 2-Py Me PhCH₂O H H1-33 2-Py Me OH PhCO H

[0503] TABLE 2

Example Number R³ R¹ Ring A 1-28 2-Py Me

1-29 2-Py Me

1-30 2-Py Me

EXAMPLE 1-34

[0504] 4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0505] A solution of2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50.2 g,0.17 mol) in phosphorous oxychloride (120 mL, 1.27 mol) was heated underreflux for 1 hour. After the solution was cooled to room temperature,the solvent was evaporated under reduced pressure and the residue waspoured into iced water. The solution was made basic by the addition of asodium hydroxide solution, and organic matter was extracted withchloroform. The extract was washed with saturated brine and water, driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. Purification of the residue thus obtained by silicagel column chromatography (chloroform:methanol=98:2) gave the titlecompound (21.5 g, 43% yield).

[0506] mp: 157-159° C. (recrystallized from ethyl acetate/hexane).

[0507] NMR (CDCl₃) δ: 3.00 (3H, s), 7.21-7.25 (1H, m), 7.60-7.64 (1H,m), 7.78-7.87 (1H, m), 7.90-7.99 (1H, m), 8.18 (1H, dd, J=0.8 Hz, 8.4Hz), 8.41 (1H, dt, J=0.8 Hz, 7.6 Hz), 8.68 (1H, d, J=4.8 Hz), 8.85 (1H,d, J=8.4 Hz).

[0508] Elementary Analysis: for C₁₆H₁₁ClN₄

[0509] Calcd.: C, 65.20; H, 3.76; N, 19.01; Cl, 12.03.

[0510] Found: C, 65.22; H, 3.73; N, 19.13; Cl, 11.76.

EXAMPLE 1-35

[0511] 3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0512] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.44 g,4.89 mmol) and sodium azide (0.35 g, 5.37 mmol) in N,N-dimethylformamide(10 mL) was heated and stirred at 100° C. for 30 minutes. The solutionwas cooled to room temperature and poured into water, and organic matterwas extracted with chloroform. The extract was washed with saturatedbrine and water, dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. To a solution of the residue thusobtained in ethanol (70 mL) was added 10% palladium-carbon (2 g, 50%hydrate), and the mixture was stirred at room temperature for 1 hourunder an hydrogen atmosphere. The catalyst was removed by filtration,and the filtrate was concentrated under reduced pressure. The resultingresidue was purified by basic silica gel column chromatography (ethylacetate:methanol=95:5) to give the title compound (760 mg, 57% yield).

[0513] mp: 210-213° C. (recrystallized from methanol/ethylacetate/hexane).

[0514] NMR (CDCl₃) δ: 2.80 (3H, s), 5.60 (2H, br s), 7.13-7.22 (1H, m),7.29-7.40 (1H, m), 7.63-7.75 (1H, m), 7.80-7.95 (2H, m), 7.98-8.05 (1H,m), 8.60-8.67 (1H, m), 8.90-8.98 (1H, m).

[0515] Elementary Analysis: for C₁₆H₁₃N₅

[0516] Calcd.: C, 69.80; H, 4.76; N, 25.44.

[0517] Found: C, 69.61; H, 4.70; N, 25.30.

EXAMPLE 1-36

[0518] 3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[0519] To a solution of3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine (1.56 g,5.65 mmol) in ethanol (5 mL) was added a 4N hydrochloric acid/ethylacetate solution (10 mL), and the solution was concentrated underreduced pressure. The residue thus obtained was recrystallized fromethanol to give the title compound (1.41 g, 80% yield).

[0520] mp: 268-271° C. (recrystallized from ethanol).

[0521] NMR (DMSO-d₆) δ: 2.85 (3H, s), 7.46-7.52 (1H, m), 7.59-7.67 (1H,m), 7.92-8.04 (2H, m), 8.09-8.18 (1H, m), 8.44 (1H, d, J=8.4 Hz),8.68-8.70 (1H, m), 8.82-8.87 (2H, m), 9.85 (2H, br s).

[0522] Elementary Analysis: for C₁₆H₁₃N₅.HCl.1.6H₂O

[0523] Calcd.: C, 56.42; H, 5.09; N, 20.56; Cl, 10.41.

[0524] Found: C, 56.20; H, 5.01; N, 20.60; Cl, 10.39.

EXAMPLE 1-37

[0525]N-Methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]aminehydrochloride

[0526] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.8 g,2.71 mmol) in 40% methylamine methanol (21 mL, 0.27 mol) solution washeated and stirred at 100° C. for 4 hours in a sealed stainless tube.After the solution was cooled to room temperature, the reaction solventswere evaporated under reduced pressure. Purification of the residue thusobtained by silica gel column chromatography (chloroform:methanol=98:2)gave an oil ofN-methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine.To a solution of the oil in ethanol (10 mL), was added a saturatedhydrochloric acid/ethanol solution (10 mL), and the solution wasconcentrated under reduced pressure. The residue thus obtained wasrecrystallized from methanol/ethyl acetate to give the title compound(0.63 g, 64% yield).

[0527] mp: 229-232° C. (recrystallized from ethyl acetate/methanol).

[0528] NMR (DMSO-d₆) δ: 2.84 (3H, s), 3.57 (3H, s), 7.45-7.62 (2H, m),7.87-8.00 (2H, m), 8.14 (1H, d, J=7.3 Hz, 1.8 Hz), 8.34 (1H, d, J=8.1Hz), 8.55-8.71 (1H, m), 8.72-8.82 (1H, m), 10.40 (1H, br s).

[0529] Elementary Analysis: for C₁₇H₁₅N₅.1.5HCl.H₂O

[0530] Calcd.: C, 56.40; H, 5.15; N, 19.34.

[0531] Found: C, 56.29; H, 5.10; N, 19.08.

EXAMPLE 1-38

[0532]N,N-Dimethyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine

[0533] 4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(1.00 g, 3.39 mmol) was added to a 2M dimethylamine tetrahydrofuran(5.00 mL, 10.0 mmol) solution, and the mixture was heated at 100° C.overnight in a sealed tube. The reaction mixture was cooled to roomtemperature and poured into water, and organic matter was extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (ethyl acetate to ethyl acetate:methanol=9:1) togive the title compound (1.00 g, 97% yield).

[0534] mp: 98-101° C. (recrystallized from ethyl acetate/hexane).

[0535] NMR (CDCl₃) δ: 2.89 (3H, s), 3.39 (6H, s), 7.16-7.22 (1H, m),7.37-7.45 (1H, m), 7.66-7.74 (1H, m), 7.87-7.96 (1H, m), 8.12 (1H, d,J=9.0 Hz), 8.22 (1H, d, J=7.3 Hz), 8.64-8.67 (1H, m), 8.94 (1H, d, J=8.4Hz).

[0536] Elementary Analysis: for C₁₈H₁₇N₅

[0537] Calcd.: C, 71.27; H, 5.65; N, 23.09.

[0538] Found: C, 71.25; H, 5.64; N, 23.02.

EXAMPLE 1-39

[0539]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0540] A mixture of methanesulfonic acid (120 mL, 0.84 mol) andphosphorus pentoxide (24.0 g, 0.17 mol) was heated at 100° C. Themixture was stirred thoroughly at the same temperature, with the gradualaddition of powdery2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (24.0 g,82 mmol). The reaction mixture was heated and stirred at the sametemperature further for 15 minutes. The mixture was allowed to cool toroom temperature, and water was added thereto. The solution was madebasic by the addition of an aqueous sodium hydroxide solution, andorganic matter was extracted with chloroform. The extract was washedwith saturated brine and water, dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue thusobtained was purified by basic silica gel column chromatography(chloroform). The crystals thus obtained wedissolved in a mixture ofethyl acetate (300 mL) and methanol (300 mL) under heating, and heatedunder reflux for 30 minutes after the addition of activated carbon (2.5g). The hot solution was filtered, and the solvents were evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate to give the title compound (15.1 g, 67% yield).

[0541] mp: 199-200° C. (recrystallized from ethyl acetate).

[0542] NMR (CDCl₃) δ: 2.77 (3H, s), 7.19-7.26 (1H, m), 7.33 (1H, td,J=1.2 Hz, 8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.61-7.70 (1H, m), 7.90 (1H,td, J=8.4 Hz, 1.6 Hz), 8.02 (1H, d, J=8.4 Hz), 8.46-8.50 (2H, m), 11.45(1H, br s).

[0543] Elementary Analysis: for C₁₆H₁₂N₄O

[0544] Calcd.: C, 69.55; H, 4.38; N, 20.28.

[0545] Found: C, 69.47; H, 4.26; N, 20.33.

EXAMPLE 1-40

[0546]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0547] To a solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (34.9 g,0.12 mol) in ethanol (500 mL) was added 6N hydrochloric acid (50 mL,0.30 mol), and the mixture was heated and under reflux for 2 hours. Thesolution was cooled to room temperature, and the reaction solvent wasconcentrated and evaporated under reduced pressure. The residue was madebasic by the addition of an aqueous sodium hydroxide solution, andorganic matter was extracted with chloroform. The extract was washedwith saturated brine and water, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(chloroform:methanol=95:5) to give the title compound (25.8 g, 79%yield).

EXAMPLE 1-41

[0548] 4-Butoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0549] To an ice-cold solution of 1-butanol (5.0 g, 68 mmol) intetrahydrofuran (15 mL) was added sodium hydride (oiliness, content 60%,0.41 g, 17 mmol), and the mixture was stirred at room temperature for 15minutes. After4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g,3.39 mmol) was added thereto at 0° C., the mixture was heated underreflux further for 1 hour. The reaction mixture was allowed to cool toroom temperature, and the solvent was evaporated and concentrated underreduced pressure. Iced water was added to the residue and the mixturewas neutralized with dilute hydrochloric acid, and organic matter wasextracted with ethyl acetate. The extract was washed with saturatedbrine and water, dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (ethyl acetate) to give thetitle compound (0.29 g, 26% yield).

[0550] mp: 59-61° C. (recrystallized from petroleum ether/hexane).

[0551] NMR (CDCl₃) δ: 1.06 (3H, t, J=7.3 Hz), 1.56-1.75 (2H, m),1.95-2.10 (2H, m), 2.91 (3H, s), 4.37 (2H, t, J=6.6 Hz), 7.16-7.26 (1H,m), 7.43-7.54 (1H, m), 7.72-7.84 (1H, m), 7.88-7.98 (1H, m), 8.15 (1H,d, J=8.4 Hz), 8.31 (1H, d, J=8.4 Hz), 8.64-8.70 (1H, m), 8.92 (1H, d,J=8.4 Hz).

EXAMPLE 1-42

[0552]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-thione

[0553] A solution of3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(13.94 g, 50.5 mmol) and Lawesson's Reagent (12.5 g, 30.9 mmol) intoluene (750 mL) was heated under reflux for 1 hour. The solution wascooled to room temperature, and the resulting crude crystals werecollected by filtration. The crystals were recrystallized from ethylacetate to give the title compound (13.11 g, 89% yield).

[0554] mp: 252-253° C. (recrystallized from ethyl acetate).

[0555] NMR (CDCl₃) δ: 2.96 (3H, s), 7.23-7.28 (1H, m), 7.37-7.50 (2H,m), 7.65-7.73 (1H, m), 7.88-7.97 (1H, m), 8.05 (1H, d, J=7.6 Hz), 8.51(1H, d, J=4.2 Hz), 9.08 (1H, d, J=8.6 Hz), 12.01 (1H, br s).

[0556] Elementary Analysis: for C₁₆H₁₂N₄S

[0557] Calcd.: C, 65.73; H, 4.14; N, 19.16.

[0558] Found: C, 65.53; H, 4.10; N, 19.04.

EXAMPLE 1-43

[0559] 4-Chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0560] To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol)in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise atroom temperature, and the mixture was stirred overnight at roomtemperature. The reaction solvent and excess diketene was evaporatedunder reduced pressure. To the residue, carbon tetrachloride (80 mL) andsubsequently acetic anhydride (27 g, 0.265 mol) were added, and themixture was heated under reflux for 3 hours. The reaction solvent andexcess acetic anhydride were evaporated and concentrated under reducedpressure, and the resulting powder was collected by filtration andwashed with diethylether to give crude5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). Asolution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine(7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1hour. The reaction solution was allowed to cool to room temperature, andthe reaction solvent was evaporated and concentrated under reducedpressure. A solution of the residue in phosphorous oxychloride (45.8 g,0.3 mol) was heated and stirred at 100° C. for 1 hour. After thereaction solution was cooled to room temperature, the reaction solventwas evaporated and concentrated under reduced pressure, and the residuewas poured into iced water, which was made basic by the addition of asodium hydroxide solution, and organic matter was extracted withchloroform. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (ethyl acetate:methanol=98:2) to give thetitle compound (4.4 g, 24% yield).

[0561] mp: 167-169° C. (recrystallized from ethyl acetate/methanol).

[0562] NMR (CDCl₃) δ: 2.98 (3H, s), 3.08 (3H, s), 7.18-7.33 (2H, m),7.60 (1H, q, J=7.1 Hz), 7.87-7.97 (1H, m), 8.01 (1H, d, J=8.1 Hz),8.64-8.70 (1H, m), 8.83 (1H, d, J=8.4 Hz).

[0563] Elementary Analysis: for C₁₇H₁₃ClN₄

[0564] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[0565] Found: C, 66.18; H, 4.22; N, 18.17; Cl, 11.54.

EXAMPLE 1-44

[0566] 3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0567] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (58% yield).

[0568] mp: 252-255° C. (recrystallized from methanol).

[0569] NMR (DMSO-d₆) δ: 2.82 (3H, s), 2.99 (3H, s), 6.73 (2H, br s),7.04 (1H, d, J=6.2 Hz), 7.22-7.31 (1H, m), 7.47 (1H, t, J=7.3 Hz), 7.63(1H, d, J=8.8 Hz), 7.93-8.07 (1H, m), 8.50-8.56 (1H, m), 8.71 (1H, d,J=8.4 Hz).

[0570] Elementary Analysis: for C₁₇H₁₅N₅

[0571] Calcd.: C, 70.57; H, 5.23; N, 24.21.

[0572] Found: C, 70.79; H, 5.17; N, 23.81.

EXAMPLE 1-45

[0573]3,5-Dimethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0574] A solution of4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.65g, 5.34 mmol), sodium iodide (0.96 g, 6.41 mmol) and conc. hydrochloricacid (1 mL) in dimethylsulfoxide (20 mL) was heated and stirred at 100°C. for 2 hours. The solution was cooled to room temperature, and theresidue was poured into water. The mixture was made basic by theaddition of a sodium hydroxide solution, and organic matter wasextracted with 10% methanol/chloroform. The extract was washed withsaturated brine and water, and dried over anhydrous magnesium sulfate,and the solvents were evaporated under reduced pressure. The residuethus obtained was purified by silica gel column chromatography (ethylacetate:hexane=90:10) to give the title compound (1.13 g, 73% yield).

[0575] mp: 183-186° C. (recrystallized from ethyl acetate).

[0576] NMR (CDCl₃) δ: 2.73 (3H, s), 2.99 (3H, s), 7.01 (1H, d, J=7.3Hz), 7.15-7.28 (2H, m), 7.44 (1H, t, J=7.9 Hz), 7.82-8.02 (2H, m),8.43-8.49 (1H, m), 11.18 (1H, br s).

[0577] Elementary Analysis: for C₁₇H₁₄N₄O

[0578] Calcd.: C, 70.33; H, 4.86; N, 19.36.

[0579] Found: C, 70.46; H, 4.87; N, 19.27.

EXAMPLE 1-46

[0580] 3,8-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[0581] Following the procedure described in Example 1-36, the titlecompound was prepared from3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine (57%yield).

[0582] mp: 283-286° C. (recrystallized from ethanol).

[0583] NMR (DMSO-d₆) δ: 2.59 (3H, s), 2.77 (3H, s), 3.36 (2H, br s),7.30-7.55 (2H, m), 7.62-7.82 (1H, m), 8.00-8.20 (2H, m), 8.50-8.70 (2H,m).

[0584] Elementary Analysis: for C₁₇H₁₅N₅.HCl.0.5H₂O

[0585] Calcd.: C, 60.99; H, 5.12; N, 20.92; Cl, 10.59.

[0586] Found: C, 61.38; H, 4.96; N, 20.71; Cl, 10.64.

EXAMPLE 1-47

[0587]3,8-Dimethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0588] Following the procedure described in Example 1-40, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (72%yield).

[0589] mp: 241-243° C. (recrystallized from ethanol).

[0590] NMR (CDCl₃) δ: 2.57 (3H, s), 2.75 (3H, s), 7.17-7.30 (2H, m),7.49 (1H, d, J=7.3 Hz), 7.84-7.92 (1H, m), 8.00 (1H, d, J=8.4 Hz), 8.32(1H, d, J=7.3 Hz), 8.46 (1H, d, J=4.0 Hz), 11.59 (1H, br s).

[0591] Elementary Analysis: for C₁₇H₁₄N₄O

[0592] Calcd.: C, 70.33; H, 4.86; N, 19.36.

[0593] Found: C, 70.25; H, 4.65; N, 19.21.

EXAMPLE 1-48

[0594]8-Methoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[0595] Following the procedures described in Examples 1-35 and 1-36, thetitle compound was prepared from4-chloro-8-methoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (65% yield).

[0596] mp: 248-251° C. (recrystallized from ethanol).

[0597] NMR (DMSO-d₆) δ: 2.73 (3H, s), 4.10 (3H, s), 7.53-7.60 (3H, m),7.85 (1H, d. J=8.4 Hz), 8.03-8.20 (2H, m), 8.53 (1H, br d, J=5.1 Hz),hidden (2H).

[0598] Elementary Analysis: for C₁₇H₁₅N₅O.HCl.1.5H₂O

[0599] Calcd.: C, 55.36; H, 5.19; N, 18.99; Cl, 9.61.

[0600] Found: C, 55.32; H, 4.95; N, 18.86; Cl, 9.54.

EXAMPLE 1-49

[0601]6,7-Dimethoxy-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0602] Following the procedure described in Example 1-39, the titlecompound was prepared from4,5-dimethoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (35% yield).

[0603] mp: 238-239° C. (recrystallized from ethyl acetate/methanol).

[0604] NMR (DMSO-d₆) δ: 2.60 (3H, s), 3.85 (3H, s), 3.93 (3H, s),7.35-7.42 (1H, m), 7.56 (1H, s), 7.66 (1H, s), 7.88 (1H, d, J=8.4 Hz),8.05 (1H, ddd, J=8.4 Hz, 7.4 Hz, 1.8 Hz), 8.59-8.61 (1H, m), 11.78 (1H,br s).

[0605] Elementary Analysis: for C₁₈H₁₆N₄O₃.H₂O

[0606] Calcd.: C, 61.01; H, 5.12; N, 15.81.

[0607] Found: C, 60.81; H, 5.12; N, 15.86.

EXAMPLE 1-50

[0608]3-Methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0609] Following the procedure described in Example 1-39, the titlecompound was prepared from6-(methylsulfanyl)-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (50% yield).

[0610] mp: 182-185° C. (recrystallized from methanol/ethyl acetate).

[0611] NMR (CDCl₃) δ: 2.58 (3H, s), 2.74 (3H, s), 7.17-7.25 (1H, m),7.35 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J=2.2 Hz, 8.8 Hz), 7.83-7.93 (1H,m), 7.99 (1H, d, J=8.8 Hz), 8.27 (1H, d, J=2.2 Hz), 8.43-8.49 (1H, m),11.42 (1H, br s).

[0612] Elementary Analysis: for C₁₇H₁₄N₄OS

[0613] Calcd.: C, 63.33; H, 4.38; N, 17.38.

[0614] Found: C, 62.92; H, 4.38; N, 17.09.

EXAMPLE 1-51

[0615]6-Chloro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0616] Following the procedure described in Example 1-40, the titlecompound was prepared from4,6-dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (84%yield).

[0617] mp: 254-255° C. (recrystallized from ethanol).

[0618] NMR (DMSO-d₆) δ: 2.59 (3H, s), 7.37-7.44 (1H, m), 7.74 (1H, dd,J=2.6 Hz, 9.2 Hz), 7.88 (1H, d, J=8.4 Hz), 8.02-8.13 (3H, m), 8.59-8.61(1H, m), 12.05 (1H, br s).

[0619] Elementary Analysis: for C₁₆H₁₁ClN₄O

[0620] Calcd.: C, 61.84; H, 3.57; N, 18.03; Cl, 11.41.

[0621] Found: C, 61.80; H, 3.61; N, 18.16; Cl, 11.36.

EXAMPLE 1-52

[0622]4-Chloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0623] Following the procedures described in Reference Example 1-11 andExample 1-34, the title compound was prepared from5-fluoro-2-iodobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (57% yield).

[0624] mp: 185-187° C. (recrystallized from ethyl acetate).

[0625] NMR (DMSO-d₆) δ: 3.00 (3H, s), 7.21-7.28 (1H, m), 7.62 (1H, ddd,J=3.0 Hz, 5.4 Hz, 9.4 Hz), 7.89-7.99 (2H, m), 8.19 (1H, dd, J=5.4 Hz,9.4 Hz), 8.69 (1H, d, J=3.6 Hz), 8.77 (1H, d, J=8.2 Hz).

[0626] Elementary Analysis: for C₁₆H₁₀ClFN₄O

[0627] Calcd.: C, 61.45; H, 3.22; N, 17.92; Cl, 11.34; F, 6.08.

[0628] Found: C, 61.60; H, 3.10; N, 17.62; Cl, 11.22; F, 5.80.

EXAMPLE 1-53

[0629]6-Fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0630] Following the procedure described in Example 1-40, the titlecompound was prepared from4-chloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(51% yield).

[0631] mp: 278-280° C. (recrystallized from ethanol/tetrahydrofuran).

[0632] NMR (CDCl₃) δ: 2.75 (3H, s), 7.16-7.27 (1H, m), 7.33-7.48 (2H,m), 7.87-8.14 (3H, m), 8.48 (1H, d, J=5.2 Hz), 11.51 (1H, s)

[0633] Elementary Analysis: for C₁₆H₁₁FN₄O

[0634] Calcd. : C, 65.30; H, 3.77; N, 19.04; F, 6.46.

[0635] Found: C, 65.32; H, 3.83; N, 18.99; F, 6.17.

EXAMPLE 1-54

[0636]3-Methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0637] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3-methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (52% yield).

[0638] mp: 229-232° C. (recrystallized from ethyl acetate/methanol).

[0639] NMR (CDCl₃) δ: 2.38 (3H, s), 2.87 (3H, s), 5.60 (2H, br s),7.25-7.38 (1H, m), 7.62-7.74 (2H, m), 7.84 (1H, d, J=8.8 Hz), 8.00 (1H,d, J=8.8 Hz), 8.44 (1H, s), 8.75 (1H, d, J=8.4 Hz).

[0640] Elementary Analysis: for C₁₇H₁₅N₅

[0641] Calcd.: C, 70.57; H, 5.23; N, 24.21.

[0642] Found: C, 70.37; H, 5.51; N, 23.97.

EXAMPLE 1-55

[0643]3-Methyl-1-(5-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-onehydrochloride

[0644] Following the procedure described in Example 1-40, the titlecompound was prepared from4-chloro-3-methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(51% yield).

[0645] mp: 227-229° C. (recrystallized from ethanol).

[0646] NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.61 (3H, s), 7.33 (1H, t, J=7.5Hz), 7.66-7.92 (3H, m), 8.03 (1H, d, J=8.4 Hz), 8.22 (1H, d, J=7.0 Hz),8.43 (1H, s), 11.85 (1H, s).

[0647] Elementary Analysis: for C₁₇H₁₄N₄.HCl.0.5H₂O

[0648] Calcd.: C, 60.81; H, 4.80; N, 16.68.

[0649] Found: C, 60.65; H, 5.25; N, 16.66.

EXAMPLE 1-56

[0650]4-Chloro-3-methyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0651] Following the procedures described in Reference Example 1-10 andExample 1-34, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazino-3-methylpyridine(21% yield).

[0652] mp: 160-161° C. (recrystallized from ethyl acetate/hexane).

[0653] NMR (CDCl₃) δ: 2.37 (3H, s), 2.98 (3H, s), 7.37 (1H, dd, J=4.8Hz, 7.6 Hz), 7.52-7.60 (1H, m), 7.72-7.83 (2H, m), 8.05 (1H, td, J=0.8Hz, 8.8 Hz), 8.39-8.44 (1H, m), 8.54-8.57 (1H, m).

[0654] Elementary Analysis: for C₁₇H₁₃ClN₄

[0655] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[0656] Found: C, 66.13; H, 4.28; N, 18.12; Cl, 11.51.

EXAMPLE 1-57

[0657]4-Chloro-3,5-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0658] Following the procedure described in Example 1-43, the titlecompound was prepared from 2-amino-6-methylbenzoic acid and6-ethoxy-2-hydrazinopyridine synthesized from 2-chloro-6-ethoxypyridine(32% yield).

[0659] mp: 146-148° C. (recrystallized from ethyl acetate).

[0660] NMR (CDCl₃) δ: 1.48 (3H, t, J=7.0 Hz), 2.96 (3H, s), 3.13 (3H,s), 4.57 (2H, q, J=7.0 Hz), 6.69 (1H, d, J=8.1 Hz), 7.31 (1H, d, J=7.0Hz), 7.63 (1H, t, J=7.0 Hz), 7.78 (1H, t, J=7.7 Hz), 7.96 (1H, d, J=7.7Hz), 8.12 (1H, d, J-8.1 Hz).

[0661] Elementary Analysis: for C₁₉H₁₇ClN₄O

[0662] Calcd.: C, 64.68; H, 4.86; N, 15.88.

[0663] Found: C, 64.62; H, 4.81; N, 16.10.

EXAMPLE 1-58

[0664]4-Chloro-3,8-dimethyl-1-(6-methoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0665] Following the procedures described in Reference Example 1-10 andExample 1-34, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazino-6-methoxypyridine which was prepared from2-chloro-6-methoxypyridine following the procedure described inReference Example 1-9 (75% yield).

[0666] mp: 148-151° C. (recrystallized from chloroform/hexane).

[0667] NMR (CDCl₃) δ: 2.87 (3H, s), 2.97 (3H, s), 4.15 (3H, s), 6.69(1H, d, J=8.1 Hz), 7.47 (1H, dd, J=6.8 Hz, 8.6 Hz), 7.64-7.71 (1H, m),7.80 (1H, t, J=8.1 Hz), 8.20-8.30 (2H, m).

[0668] Elementary Analysis: for C₁₈H₁₅ClN₄O

[0669] Calcd.: C, 63.81; H, 4.46; N, 16.54.

[0670] Found: C, 63.87; H, 4.44; N, 16.46.

EXAMPLE 1-59

[0671]3,8-Dimethyl-1-(6-methoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0672] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(6-methoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (46% yield).

[0673] mp: 134-137° C. (recrystallized from ethyl acetate/hexane).

[0674] NMR (CDCl₃) δ: 2.80 (3H, s), 2.86 (3H, s), 4.13 (3H, s), 5.50(2H, br s), 6.63 (1H, d, J=8.1 Hz), 7.20-7.30 (1H, m), 7.56 (1H, d,J=6.6 Hz), 7.70 (1H, d, J=6.6 Hz), 7.78 (1H, t, J=8.1 Hz), 8.44 (1H, d,J=7.7 Hz).

[0675] Elementary Analysis: for C₁₈H₁₇N₅O.H₂O

[0676] Calcd.: C, 64.08; H, 5.68; N, 20.76.

[0677] Found: C, 64.17; H, 5.43; N, 20.36.

EXAMPLE 1-60

[0678]3,8-Dimethyl-1-(6-ethoxy-2-pyridinyl-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0679] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (82% yield).

[0680] mp: 184-187° C. (recrystallized from chloroform).

[0681] NMR (CDCl₃) δ: 1.45 (3H, t, J=7.0 Hz), 2.81 (3H, s), 2.87 (3H,s), 4.56 (2H, q, J=7.0 Hz), 5.47 (2H, br s), 6.61 (1H, d, J=8.0 Hz),7.25 (1H, q, J=7.0 Hz), 7.57 (1H, d, J=7.0 Hz), 7.70 (1H, d, J=8.0 Hz),7.79 (1H, t, J=8.0 Hz), 8.43 (1H, d, J=8.0 Hz).

[0682] Elementary Analysis: for C₁₉H₁₉N₅O

[0683] Calcd.: C, 68.45; H, 5.74; N, 21.01.

[0684] Found: C, 68.33; H, 6.00; N, 20.95.

EXAMPLE 1-61

[0685]3,8-Dimethyl-1-(6-ethoxy-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0686] Following the procedure described in Example 1-40, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(73% yield).

[0687] mp: 239-241° C. (recrystallized from chloroform).

[0688] NMR (CDCl₃) δ: 1.51 (3H, t, J=7.0 Hz), 2.52 (3H, s), 2.72 (3H,s), 4.40 (2H, q, J=7.0 Hz), 6.60 (1H, dd, J=0.74 Hz, 8.1 Hz), 7.18 (1H,t, J=8.1 Hz), 7.40-7.48 (1H, m), 7.53 (1H, dd, J=0.74 Hz, 8.1 Hz), 7.73(1H, t, J=8.1 Hz), 8.30 (1H, d, J=7.3 Hz), 10.9 (1H, br s).

[0689] Elementary Analysis: for C₁₉H₁₈N₄O₂

[0690] Calcd.: C, 68.25; H, 5.43; N, 16.76.

[0691] Found: C, 68.08; H, 5.59; N, 16.60.

EXAMPLE 1-62

[0692]3,8-Dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0693] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (68% yield).

[0694] mp: 199-202° C. (recrystallized from ethyl acetate).

[0695] NMR (CDCl₃) δ: 2.43 (3H, s), 2.61 (3H, s), 2.76 (3H, s), 5.51(2H, br s), 7.16 (1H, t, J=7.7 Hz), 7.30 (1H, dd, J=4.8 Hz, 7.7 Hz),7.48 (1H, d, J=6.6 Hz), 7.67 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=7.7 Hz),8.52 (1H, dd, J=1.5 Hz, 4.8 Hz).

[0696] Elementary Analysis: for C₁₈H₁₇N₅

[0697] Calcd.: C, 71.27; H, 5.65; N, 23.09.

[0698] Found: C, 71.23; H, 5.60; N, 22.87.

EXAMPLE 1-63

[0699] 3-Methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminedihydrochloride

[0700] Following the procedures described in Examples 1-35 and 1-36, thetitle compound was prepared from4-chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and sodiumazide (72% yield).

[0701] mp: 234-237° C. (recrystallized from methanol).

[0702] NMR (DMSO-d₆) δ: 2.83 (3H, s), 7.53 (1H, t, J=8.1 Hz), 7.83-8.05(3H, m), 8.58-8.85 (3H, m), 9.00 (2H, br s), 9.32 (1H, br s).

[0703] Elementary Analysis: for C₁₆H₁₃N₅.2HCl.2H₂O

[0704] Calcd.: C, 50.01; H, 4.98; N, 18.23; Cl, 18.45.

[0705] Found: C, 49.98; H, 5.05; N, 18.18; Cl, 18.27.

EXAMPLE 1-64

[0706]3-Methyl-1-(3-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0707] Following the procedure described in Example 1-40, the titlecompound was prepared from4-chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (37%yield).

[0708] mp: 282-283° C. (recrystallized from ethanol).

[0709] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.26-7.34 (1H, m), 7.66-7.72 (3H,m), 8.15 (1H, ddd, J=1.4 Hz, 2.6 Hz, 8.2 Hz), 8.22 (1H, d, J=8.2 Hz),8.73 (1H, dd, J=1.4 Hz, 4.6 Hz), 8.96 (1H, d, J=2.6 Hz), 11.93 (1H, brs).

[0710] Elementary Analysis: for C₁₆H₁₂N₄O.0.5H₂O

[0711] Calcd.: C, 67.36; H, 4.59; N, 19.64.

[0712] Found: C, 67.50; H, 4.83; N, 19.61.

EXAMPLE 1-65

[0713] 3-Methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[0714] Following the procedures described in Examples 1-35 and 1-36, thetitle compound was prepared from4-chloro-3-methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (53% yield).

[0715] mp: 287-290° C. (recrystallized from methanol).

[0716] NMR (DMSO-d₆) δ: 2.84 (3H, s), 7.50-7.63 (2H, m), 7.87-7.98 (1H,m), 8.29 (1H, d, J=8.4 Hz), 8.73 (1H, d, J=8.1 Hz), 8.92 (2H, br s),9.00 (2H, d, J=4.8 Hz).

[0717] Elementary Analysis: for C₁₅H₁₂N₆.HCl.3H₂O

[0718] Calcd.: C, 49.12; H, 5.22; N, 22.91.

[0719] Found: C, 49.53; H, 4.94; N, 22.83.

EXAMPLE 1-66

[0720]3,8-Dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0721] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (42% yield).

[0722] mp: 273-276° C. (recrystallized from ethyl acetate/methanol).

[0723] NMR (CDCl₃) δ: 2.84 (3H, s), 2.93 (3H, s), 5.86 (2H, br s),7.22-7.30 (1H, m), 7.48 (1H, t, J=7.0 Hz), 7.58 (1H, d, J=7.0 Hz), 7.70(1H, t, J=1.5 Hz, 7.0 Hz), 7.83 (2H, d, J=8.1 Hz), 8.23 (1H, d, J=8.1Hz), 8.34 (1H, d, J=8.8 Hz), 9.46 (1H, d, J=8.8 Hz)

[0724] Elementary Analysis: for C₂₁H₁₇N₅

[0725] Calcd.: C, 74.32; H, 5.05; N, 20.63.

[0726] Found: C, 73.83; H, 4.98; N, 20.31.

EXAMPLE 1-67

[0727] 1-(2-Pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[0728] Following the procedures described in Examples 1-35 and 1-36, thetitle compound was prepared from4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and sodium azide(78% yield).

[0729] mp: 312-315° C. (recrystallized from methanol).

[0730] NMR (DMSO-d₆) δ: 7.47-7.55 (1H, m), 7.63 (1H, t, J=7.7 Hz),7.95-8.21 (3H, m), 8.45 (1H, d, J=8.4 Hz), 8.65-8.75 (2H, m), 9.11 (1H,s), 10.2 (2H, br s).

[0731] Elementary Analysis: for C₁₅H₁₁N₅.HCl

[0732] Calcd.: C, 60.51; H, 4.06; N, 23.52; Cl, 11.91.

[0733] Found: C, 60.61; H, 4.06; N, 23.30; Cl, 11.83.

EXAMPLE 1-68

[0734]3-Methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0735] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline (81%yield).

[0736] mp: 262-265° C. (recrystallized from ethanol).

[0737] NMR (DMSO-d₆) δ: 2.71 (3H, s), 6.00 (2H, s), 7.52-7.70 (3H, m),7.95-8.01 (2H, m), 8.10-8.20 (1H, m), 8.65-8.73 (2H, m), hidden (1H).

[0738] Elementary Analysis: for C₁₇H₁₅N₅.2HCl.0.5H₂O

[0739] Calcd.: C, 55.00; H, 4.89; N, 18.86; Cl, 19.10.

[0740] Found: C, 55.21; H, 4.89; N, 18.82; Cl, 19.21.

EXAMPLE 1-69

[0741]3-Methyl-1-(2-pyridinylmethyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[0742] Following the procedure described in Example 1-41, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline andmethanol (23% yield).

[0743] mp: 269-272° C. (recrystallized from ethyl acetate/methanol).

[0744] NMR (DMSO-d₆) δ: 2.51 (3H, s), 5.57 (2H, s), 7.14 (1H, d, J=8.1Hz), 7.25-7.38 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.65-7.85 (2H, m), 8.23(1H, d, J=8.1 Hz), 8.52 (1H, d, J=4.8 Hz).

[0745] Elementary Analysis: for C₁₇H₁₄N₄O

[0746] Calcd.: C, 70.33; H, 4.86; N, 19.30.

[0747] Found: C, 70.14; H, 4.80; N, 19.17.

EXAMPLE 1-70

[0748] 4-Chloro-3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0749] Following the procedures described in Reference Examples 1-10 andExample 1-34, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine(54% yield).

[0750] mp: 170-172° C. (recrystallized from ethyl acetate).

[0751] NMR (CDCl₃) δ: 2.87 (3H, s), 3.00 (3H, s), 7.20-7.28 (1H, m),7.48 (1H, dd, J=6.9 Hz, 8.4 Hz), 7.68 (1H, d, J=6.9 Hz), 7.90-8.00 (1H,m), 8.21-8.30 (1H, m), 8.65-8.73 (1H, m), 9.04 (1H, d, J=8.4 Hz).

[0752] Elementary Analysis: for C₁₇H₁₃ClN₄

[0753] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[0754] Found: C, 66.00; H, 4.08; N, 18.02; Cl, 11.43.

EXAMPLE 1-71

[0755] 3,8-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[0756] Following the procedure described in Example 1-35, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (67% yield).

[0757] mp: 208-211° C. (recrystallized from ethanol).

[0758] NMR (DMSO-d₆) δ: 2.69 (3H, s), 2.82 (3H, s), 7.15-7.32 (2H, m),7.39 (2H, br s), 7.56 (1H, d, J=6.6 Hz), 7.95-8.05 (1H, m), 8.29 (1H, d,J=8.1 Hz), 8.50-8.55 (1H, m), 8.90-9.10 (1H, m).

EXAMPLE 1-72

[0759] 4-Chloro-8-methoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0760] Following the procedures described in Reference Examples 1-10 andExample 1-34, the title compound was prepared from8-methoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinopyridine (23% yield).

[0761] mp: 167-169° C. (recrystallized from ethyl acetate).

[0762] NMR (CDCl₃) δ: 3.00 (3H, s), 4.13 (3H, s), 7.15 (1H, d, J=7.7Hz), 7.20-7.28 (1H, m), 7.52 (1H, t, J=7.7 Hz), 7.91-8.03 (2H, m),8.65-8.71 (1H, m), 8.83 (1H, d, J=7.7 Hz).

[0763] Elementary Analysis: for C₁₇H₁₃ClN₄O

[0764] Calcd.: C, 62.87; H, 4.03; N, 17.25; Cl, 10.92.

[0765] Found: C, 62.88; H, 3.96; N, 17.16; Cl, 10.90.

EXAMPLE 1-73

[0766] 4,6-Dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0767] Following the procedures described in Reference Examples 1-10 andExample 1-34, the title compound was prepared from6-chloro-2-(2-oxypropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine(5% yield).

[0768] mp: 233-235° C. (recrystallized from ethyl acetate/methanol).

[0769] NMR (CDCl₃) δ: 2.99 (3H, s), 7.22-7.29 (1H, m), 7.74 (1H, dd,J=2.6 Hz, 9.0 Hz), 7.89-7.98 (1H, m), 8.12 (1H, d, J=9.0 Hz), 8.37 (1H,d, J=2.2 Hz), 8.67-8.69 (1H, m), 8.75 (1H, d, J=8.0 Hz).

[0770] Elementary Analysis: for C₁₆H₁₀Cl₂N₄

[0771] Calcd.: C, 58.38; H, 3.06; N, 17.02; Cl, 21.54.

[0772] Found: C, 58.54; H, 3,06; N, 17.02; Cl, 21.48.

EXAMPLE 1-74

[0773]4-Chloro-3-methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0774] Following the procedure described in Example 1-43, the titlecompound was prepared from anthranilic acid and2-hydrazino-5-methylpyridine which was separately prepared from2-bromo-5-methylpyridine following the method described in ReferenceExample 1-9 (22% yield).

[0775] mp: 197-200° C. (recrystallized from ethyl acetate/methanol).

[0776] NMR (CDCl₃) δ: 2.42 (3H, s), 3.00 (3H, s), 7.53-7.64 (1H, m),7.71-7.87 (2H, m), 8.16 (1H, d, J=8.8 Hz), 8.36-8.43 (1H, m), 8.46-8.52(1H, m), 8.66 (1H, d, J=8.8 Hz).

[0777] Elementary Analysis: for C₁₇H₁₃ClN₄

[0778] Calcd.: C, 66.13; H, 4.24; N, 18.15.

[0779] Found: C, 66.16; H, 4.30; N, 18.10.

EXAMPLE 1-75

[0780]4-Chloro-3,8-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0781] Following the procedures described in Reference Example 1-10 andExample 1-34, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and6-ethoxy-2-hydrazinopyridine which was separately prepared from2-chloro-6-ethoxypyridine following the method described in ReferenceExample 1-9 (62% yield).

[0782] mp: 151-153° C. (recrystallized from ethyl acetate).

[0783] NMR (CDCl₃) δ: 1.46 (3H, t, J=7.1 Hz), 2.86 (3H, s), 2.96 (3H,s), 4.60 (2H, q, J=7.1 Hz), 6.66 (1H, dd, J=0.73 Hz, 8.1 Hz), 7.46 (1H,q, J=7.0 Hz), 7.63-7.70 (1H, m), 7.79 (1H, t, J=8.1 Hz), 8.15-8.28 (2H,m).

[0784] Elementary Analysis: for C₁₉H₁₇ClN₄O

[0785] Calcd,: C, 64.68; H, 4.86; N, 15.88; Cl, 10.05.

[0786] Found: C, 64.54; H, 5.07; N, 15.69; Cl, 10.04.

EXAMPLE 1-76

[0787]4-Chloro-3,8-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0788] Following the procedures described in Reference Example 1-10 andExample 1-34, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazino-3-methylpyridine (57% yield).

[0789] mp: 182-185° C. (recrystallized from chloroform/methanol).

[0790] NMR (CDCl₃) δ: 2.42 (3H, s), 2.70 (3H, s), 2.99 (3H, s),7.32-7.50 (2H, m), 7.62 (1H, d, J=6.6 Hz), 7.77-7.85 (1H, m), 8.26 (1H,d, J=8.8 Hz), 8.54 (1H, dd, J=1.5 Hz, 4.4 Hz).

[0791] Elementary Analysis: for C₁₈H₁₅ClN₄

[0792] Calcd.: C, 66.98; H, 4.68; N, 17.36.

[0793] Found: C, 67.10; H, 4.61; N, 17.13.

EXAMPLE 1-77

[0794] 4-Chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0795] Following the procedure described in Example 1-34, the titlecompound was prepared from2-[[3-methyl-1-(3-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50%yield).

[0796] mp: 144-145° C. (recrystallized from ethyl acetate).

[0797] NMR (CDCl₃) δ: 2.93 (3H, s), 7.46 (1H, dd, J=4.8 Hz, 8.2 Hz),7.52-7.60 (1H, m), 7.76-7.84 (1H, m), 8.11 (1H, d, J=8.2 Hz), 8.33-8.38(1H, m), 8.53 (1H, dd, J=1.4 Hz, 4.8 Hz), 8.81 (1H, ddd, J=1.4 Hz, 2.6Hz, 8.4 Hz), 9.79-9.80 (1H, m).

[0798] Elementary Analysis: for C₁₆H₁₁ClN₄

[0799] Calcd.: C, 65.20; H, 3.76; N, 19.01; Cl, 12.03.

[0800] Found: C, 65.22; H, 3.73; N, 19.13; Cl, 11.91.

EXAMPLE 1-78

[0801] 4-Chloro-3-methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinoline

[0802] Following the methods described in Reference Example 1-10 andExample 1-34, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyrimidine (69%yield).

[0803] mp: 257-260° C. (recrystallized from ethyl acetate).

[0804] NMR (CDCl₃) δ: 2.80 (3H, s), 7.24-7.36 (2H, m), 7.54-7.73 (2H,m), 8.43-8.50 (1H, m), 8.89 (2H, dd, J=1.5 Hz, 5.1 Hz).

[0805] Elementary Analysis: for C₁₅H₁₀ClN₅

[0806] Calcd.: C, 60.92; H, 3.41; N, 23.68; Cl, 11.99.

[0807] Found: C, 60.63; H, 3.49; N, 23.59; Cl, 11.79.

EXAMPLE 1-79

[0808]4-Chloro-3,8-dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinoline

[0809] Following the procedures described in Reference Example 1-10 andExample 1-34, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinoquinoline which was separately prepared from2-chloroquinoline following the method described in Reference Example1-9 (42% yield).

[0810] mp: 165-168° C. (recrystallized from methanol/chloroform).

[0811] NMR (CDCl₃) δ: 2.91 (3H, s), 3.04 (3H, s), 7.44-7.57 (2H, m),7.65-7.80 (2H, m), 8.10 (1H, br d, J=8.4 Hz), 8.22-8.30 (2H, m), 8.38(1H, d, J=8.8 Hz), 9.21 (1H, d, J=8.8 Hz).

EXAMPLE 1-80

[0812] 4-Chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[0813] Following the procedure described in Example 1-34, the titlecompound was prepared from2-[[l-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (49% yield).

[0814] mp: 153-156° C. (recrystallized from ethyl acetate/methanol).

[0815] NMR (CDCl₃) δ: 7.25-7.33 (1H, m), 7.58-7.67 (1H, m), 7.80-7.89(1H, m), 7.93-8.01 (1H, m), 8.23 (1H, m), 8.39 (1H, m), 8.59 (1H, s),8.70 (1H, br d, J=5.1 Hz), 8.78 (1H, d, J=8.4 Hz).

[0816] Elementary Analysis: for C₁₅H₉ClN₄

[0817] Calcd.: C, 64.18; H, 3.23; N, 19.96.

[0818] Found: C, 64.04; H, 3.01; N, 19.94.

EXAMPLE 1-81

[0819]4-Chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline

[0820] Following the procedures described in Reference Example 1-10 andExample 1-34, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinomethylpyridinewhich was separately prepared from 2-chloromethylpyridine following themethod described in Reference Example 1-9 (75% yield).

[0821] mp: 113-115° C. (recrystallized from ethyl acetate).

[0822] NMR (CDCl₃) δ: 2.89 (3H, s), 5.88 (2H, s), 6.44 (1H, d, J=7.7Hz), 7.12-7.20 (1H, m), 7.46-7.62 (2H, m), 7.70-7.80 (1H, m), 8.06 (1H,d, J=8.8 Hz), 8.33-8.40 (1H, m), 8.55-8.61 (1H, m).

[0823] Elementary Analysis: for C₁₇H₁₃ClN₄

[0824] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[0825] Found: C, 66.27; H, 4.12; N, 18.11; Cl, 11.42. TABLE 3

Example Substituent of Number R¹ R³ X Ring B 1-34 Me 2-Py Cl 1-35 Me2-Py NH₂ 1-36 Me 2-Py NH₂ 1-37 Me 2-Py MeNH 1-38 Me 2-Py Me₂N 1-41 Me2-Py ^(n)BuO 1-43 Me 2-Py Cl 1: Me 1-44 Me 2-Py NH₂ 1: Me 1-46 Me 2-PyNH₂ 4: Me 1-48 Me 2-Py NH₂ 4: MeO 1-52 Me 2-Py Cl 2: F 1-54 Me 5-Me-2-PyNH₂ 1-56 Me 3-Me-2-Py Cl 1-57 Me 6-EtO-2-Py Cl 1: Me 1-58 Me 6-MeO-2-PyCl 4: Me 1-59 Me 6-MeO-2-Py NH₂ 4: Me 1-60 Me 6-EtO-2-Py NH₂ 4: Me 1-62Me 3-Me-2-Py NH₂ 4: Me 1-63 Me 3-Py NH₂ 1-65 Me 2-Pyrimidinyl NH₂ 1-66Me 2-quinolinyl NH₂ 4: Me 1-67 H 2-Py NH₂ 1-68 Me 2-Py-CH₂ NH₂ 1-70 Me2-Py Cl 4: Me 1-71 Me 2-Py NH₂ 4: Me 1-72 Me 2-Py Cl 4: MeO 1-73 Me 2-PyCl 2: Cl 1-74 Me 5-Me-2-Py Cl 1-75 Me 6-EtO-2-Py Cl 4: Me 1-76 Me3-Me-2-Py Cl 4: Me 1-77 Me 3-Py Cl 1-78 Me 2-Pyrimidinyl Cl 1-79 Me2-quinolinyl Cl 4: Me 1-80 H 2-Py Cl 1-81 Me 2-Py-CH₂ Cl

[0826] TABLE 4

Example Substituent of Number R¹ R² R³ X Ring B 1-39 Me H 2-Py O 1-40 MeH 2-Py O 1-42 Me H 2-Py S 1-45 Me H 2-Py O 1: Me 1-47 Me H 2-Py O 4: Me1-49 Me H 2-Py O 2, 3: MeO 1-50 Me H 2-Py O 2: MeS 1-51 Me H 2-Py O 2:Cl 1-53 Me H 2-Py O 2: F 1-55 Me H 5-Me-2-Py O 1-61 Me H 6-EtO-2-Py O 4:Me 1-64 Me H 3-Py O 1-69 Me H 2-Py-CH₂ O

Formulation Example 1-1

[0827] (1) The compound obtained in Example 1-1 10.0 g (2) Lactose 60.0g (3) Cornstarch 35.0 g (4) Gelatin  3.0 g (5) Magnesium stearate  2.0 g

[0828] A mixture of the compound obtained in Example 1-1 (10.0 g),lactose (60.0 g) and cornstarch (35.0 g) was treated with 10 wt %aqueous gelatin solution (30 ml, 3.0 g as gelatin) and the resultingmixture was then granulated by sieving through a 1 mm mesh sieve, andthe resulting granules were dried at 40° C. and sieved once again. Thegranules were mixed with magnesium stearate (2.0 g) and compressed. Thecore tablets thus obtained were subsequently sugarcoated by the use ofan aqueous suspension of sucrose, titanium dioxide, talc and gum acacia.The coated tablets were glazed with beeswax to give 1000 coated tablets.

Formulation Example 1-2

[0829] (1) The compound obtained in Example 1-1 10.0 g (2) Lactose 70.0g (3) Cornstarch 50.0 g (4) Soluble starch  7.0 g (5) Magnesium stearate 3.0 g

[0830] A mixture of the compound obtained in Example 1-1 (10.0 g) andmagnesium stearate (3.0 g) was granulated by the use of an aqueoussolution of soluble starch (70 ml, 7.0 g as soluble starch), and theresulting granules were dried and mixed with lactose 70.0 g andcornstarch 50.0 g. The mixture was compressed to give 1000 tablets.

Experimental Example 1-1

[0831] Effect on Cytokine Production of Mice Sensitized byControlled-Release Ovalbumin

[0832] An osmotic pump (Alza Co., USA) containing a solution (100 μL)containing 1.0 mg of ovalbumin (OVA; albumin chicken egg grade III,Sigma Chemical) was implanted in the back of a male BALB/c mouse(Charles River) of 8 weeks old under ether anesthesia, and the mouse issensitized by the controlled-release ovalbumin. After 11 days fromimplantation of the pump, a sample of spleen was removed, and a spleniccell suspension was prepared by the use of the RPMI-1640 medium (BioWhittaker Inc., USA) containing inactivated fetal bovine serum (10% V/V;Bio Whittaker Inc., USA), 2-mercaptoethanol (50 μM), and gentamicin (20μg/ml). A sample compound (30 mg/kg b.w.) was suspended in 0.4 ml ofmethylcellulose (MC), and the suspension was orally administered, 5 daysa week during the 9-day period from the initiation day of sensitizationto the day before the day of blood sample collection (1 Group, n=10).The splenic cell suspension was adjusted to a concentration of 5.0×10⁶cells/ml, and the resulting suspension (100 μl) was pipetted onto a 96well U-bottomed plate, each of the wells containing a solution (100μl/well) of 400 μg/ml OVA, and the plate was incubated at 37° C. in a 5%carbon dioxide gas incubator for 3 days. The cultured media werecentrifuged at 200×g for 5 minutes, and the supernatants were collectedand the production of IL-4, IL-5 and IFN-γ in each of the supernatantswas determined by the ELISA method [Mouse IL-4 Bulk Kit (PerSeptiveBiosystems), Mouse IL-5 Bulk Kit (PerSeptive Biosystems), and MouseIFN-γ Bulk Kit (PerSeptive Biosystems)]. The results are shown in Table5. TABLE 5 Suppression Rate Compound (%) (Example No.) IL-4 IL-5 IFN-γExample 1-49 13.9 11.8 −9.0 Example 1-51 31.9 53.7 −11.2 Example 1-4749.9 61.1 31.8 Example 1-50 45.5 60.2 11.1 Example 1-61 16.0 26.1 −8.7Example 1-64 49.1 39.9 −6.8 Example 1-69 19.4 50.0 8.3 Example 1-56 23.712.2 12.2 Example 1-57 43.2 53.9 36.7 Example 1-36 99.8* 61.5 −130.6*Example 1-46 80.4 5.2 −132.4* Example 1-48 31.6 16.2 −7.6 Example 1-4468.2 3.1 36.3 Example 1-59 66.5 27.8 −124.0 Example 1-60 56.7 59.3 23.4Example 1-62 19.4 4.8 −13.8 Example 1-66 27.1 34.3 50.0 Example 1-65 8.116.5 −15.7

Experimental Example 1-2

[0833] Effect on Antibody Production of Mice Sensitized byControlled-Release Ovalbumin

[0834] A male BALB/c mouse (Charles River) of 7 weeks old was sensitizedby intraabdominal administration, twice at an interval of a week, of amixture of 10 μg/mouse of ovalbumin (OVA; albumin chicken egg grade III;Sigma Chemical) and 1 mg of aluminum hydroxide hydrate gel suspension(Alum; LSL Co. LTD.). After 11 days from the first sensitization, bloodwas collected from beneath eye under ether anesthesia, and the amount ofOVA-specific IgE, IgG1 (Th2 type) and IgG2a (Th1 type) antibodies in theserum were determined by the ELISA method. A sample compound (30 mg/kgb.w.) was suspended in 0.4 ml of methylcellulose (MC), and thesuspension was orally administered, 5 days a week during the 9-dayperiod from the initiation day of sensitization to the day before theday of blood sample collection (1 Group, n=8 to 10). The results areshown in Table 6. TABLE 6 Suppression Rate Compound (%) (Example No.)IgE IgG2a Example 1-47 4.9 −17.1 Example 1-50 22.0 19.5 Example 1-53 8.036.1 Example 1-55 11.7 13.7 Example 1-42 24.0 14.3 Example 1-52 41.1*39.9 Example 1-57 23.6 −55.1 Example 1-36 64.2** 23.4 Example 1-67 10.5−30.7 Example 1-37 29.6 9.6 Example 1-38 36.1 −122.4 Example 1-54 17.6−147.7 Example 1-59 60.7* 46.3 Example 1-60 54.9** 47.8 Example 1-6325.2 −5.8 Example 1-68 31.6 31.7 Example 1-29 19.1 −22.6 Example 1-146.3* 17.8 Example 1-2 29.2 −67.9 Example 1-3 19.0 −39.5 Example 1-2724.3 27.1 Example 1-25 33.9 16.5 Example 1-22 14.0 −2.1

[0835] The results in Table 6 indicate that the compound (I) of thepresent invention has an excellent inhibitory activity to IgE antibodyproduction.

Reference Example 2-1

[0836] 2-(2-Oxopropyl)-4H-3,1-benzoxazin-4-one

[0837] To a solution of anthranilic acid (290 g, 2.1 mol) in acetone(1000 mL), diketene (460 mL, 6.0 mol) was added dropwise at roomtemperature. The solution was stirred at room temperature for 16 hours,and the resulting crystals were collected by filtration, washed withacetone and diethylether, and air dried (170 g yield). The crudecrystals were suspended in a mixture of acetic anhydride (320 mL, 3.4mol) and tetrahydrofuran (1000 mL), and the suspension was heated andstirred at 80° C. for 12 hours. The suspension was cooled to roomtemperature, and concentrated under reduced pressure, and the resultingcrude crystals were collected by filtration. The crystals were washedwith acetonitrile and air dried to give the title compound (244 g, 57%yield).

[0838] mp: 120-122° C. (recrystallized from acetonitrile).

Reference Example 2-2

[0839] 2-Hydradinopyridine

[0840] According to the method described in J. Med. chem., vol.28,p.1394 (1985), the title compound was prepared. A mixture of2-chloropyridine (200 mL, 2.1 mol) and hydrazine monohydrate (400 mL,8.2 mol) was heated and refluxed for 20 hours. The solution was cooledto room temperature, excess hydrazine hydrate was evaporated underreduced pressure, and the residue was poured into water. The solutionwas made basic by the addition of a sodium hydroxide solution, andorganic matter was extracted with chloroform. The extract was washedwith saturated brine and water, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound (157 g, 68% yield). The compound was used in thefollowing process without further purification.

Reference Example 2-3

[0841] 2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0842] A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (68.2 g,0.34 mol) and 2-hydrazinopyridine (37.1 g, 0.34 mol) in ethanol (500 mL)was heated under reflux for 1 hour. After the solution was cooled toroom temperature, the resulting crystals were collected by filtration.The crystals were washed with ethanol and air dried to give the titlecompound (50.2 g, 51% yield).

[0843] mp: 190-193° C. (recrystallized from methanol).

[0844] NMR (DMSO-d₆) δ: 2.35 (3H, s), 6.15 (1H, s), 6.87-6.97 (1H, m),7.05-7.15 (1H, m), 7.46-7.56 (1H, m), 7.69 (1H, d, J=8.4 Hz), 7.73-7.82(1H, m), 7.92 (1H, d, J=8.4 Hz), 8.14 (1H, dd, J=1.5 Hz, 8.1 Hz),8.45-8.50 (1H, m), 12.25 (1H, br s).

Reference Example 2-4

[0845] 3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine

[0846] To an ice-cold solution of aminocrotononitrile (82 g, 1.0 mol)and 2-hydrazinopyridine (120 g, 1.1 mol) in ethanol (300 mL) was addedacetic acid (132 g, 2.2 mol), and the solution was heated under refluxfor 3.5 hours. The solution was cooled to room temperature, and thesolution was concentrated under reduced pressure, and water was added tothe residue. The solution was made basic by the addition of an aqueoussodium hydroxide solution, and organic matter was extracted with ethylacetate. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) to give the title compound (156.3 g, 90%yield).

[0847] mp: 103-104° C. (recrystallized from ethyl acetate).

[0848] NMR (CDCl₃) δ: 2.25 (3H, s), 5.37 (1H, s), 5.92 (2H, br s), 7.07(1H, m), 7.76 (1H, m), 7.94 (1H, d, J=7.0 Hz), 8.32 (1H, d, J=6.0 Hz).

Reference Example 2-5

[0849] 2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0850] A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (5.23g, 30 mmol), o-iodobenzoic acid (8.93 g, 36 mmol), copper acetate (II)(0.654 g, 3.6 mmol) and potassium carbonate (4.98 g, 36 mmol) inN,N-dimethylformamide (30 mL) was heated under reflux for 1 hour underan argon atmosphere. After the solution was cooled to room temperature,the mixture was poured into water. The solution was made weakly acidicby the addition of acetic acid, and the resulting crude crystals werecollected by filtration. The crystals were washed with water and airdried to give the title compound (8.64 g, 98% yield).

Reference Example 2-6

[0851] 6-Methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0852] Following the procedure described in Reference Example 2-1, thetitle compound was prepared from 2-amino-5-methylbenzoic acid (79%yield).

[0853] mp: 137-140° C. (recrystallized from ethyl acetate/hexane).

[0854] Elementary Analysis: for C₁₂H₁₁NO₃

[0855] Calcd.: C, 66.35; H, 5.10; N, 6.45.

[0856] Found: C, 66.49; H, 5.06; N, 6.22.

Reference Example 2-7

[0857]5-Methyl-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0858] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from6-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine(61% yield).

[0859] mp: 229-232° C. (recrystallized from ethanol).

[0860] NMR (DMSO-d₆) δ: 2.23 (3H, s), 2.28 (3H, s), 6.16 (1H, s),7.25-7.38 (2H, m), 7.52 (1H, d, J=8.4 Hz), 7.75 (1H, s), 7.84 (1H, dd,J=1.1 Hz, 8.4 Hz), 7.91-8.02 (1H, m), 8.41-8.47 (1H, m), 12.11 (1H, s),hidden (1H).

[0861] Elementary Analysis: for C₁₇H₁₆N₄O₂

[0862] Calcd.: C, 66.22; H, 5.23; N, 18.17.

[0863] Found: C, 66.06; H, 5.10; N, 18.29.

Reference Example 2-8

[0864] 8-Methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0865] Following the procedure described in Reference Example 2-1, thetitle compound was prepared from 2-amino-3-methylbenzoic acid (88%yield).

[0866] mp: 150-152° C. (recrystallized from ethanol).

[0867] Elementary Analysis: for C₁₂H₁₁N₄O₃

[0868] Calcd.: C, 66.35; H, 5.10; N, 6.45.

[0869] Found: C, 66.36; H, 5.12; N, 6.38.

Reference Example 2-9

[0870] 2-Chloro-5-(trifluoromethyl)benzoic acid

[0871] The title compound was prepared according to the method describedin Tetrahedron Lett., vol.37, p.2767 (1996). To a solution of1-chloro-4-(trifluoromethyl)benzene (25.8 g, 143 mmol) andtetramethylethylene diamine (16.6 g, 143 mmol) in tetrahydrofuran (250mL) cooled to -78° C., was added a solution of 1.6M butyllithium inhexane (89.4 mL, 143 mmol) was added dropwise under an argon atmosphere,and the mixture was stirred at the same temperature for 30 minutes. Thesolution was carefully poured onto crushed dry ice, and the resultingmixture was allowed to warm to room temperature. The solution wasconcentrated under reduced pressure, and the residue was poured intowater. The solution was washed with diethylether, and subsequently madeacidic by the addition of conc. hydrochloric acid, and organic matterwas extracted with dichloromethane. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue thus obtainedwas crystallized from hexane to give the title compound (20.6 g, 64%yield).

[0872] NMR (CDCl₃) δ: 7.65. (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=2.2 Hz.8.4 Hz), 8.31 (1H, d, J=2.2 Hz), hidden (1H)

Reference Example 2-10

[0873]2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-5-(trifluoromethyl)benzoicacid

[0874] A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (8.71g, 50.0 mmol), 2-chloro-5-(trifluoromethyl)benzoic acid (12.4 g, 55.0mmol), copper acetate (II) (1.00 g, 5.50 mmol) and potassium carbonate(7.60 g, 55.0 mmol) in N,N-dimethylformamide (50 mL) was heated underreflux for 1.5 hours under an argon atmosphere. The solution was cooledto room temperature, and poured into water. The solution was made acidicby the addition of acetic acid, and the resulting crude crystals werecollected by filtration. The crystals were washed with water and airdried to give the title compound (17.7 g, 89% yield).

[0875] mp: 228-229° C. (recrystallized from ethyl acetate).

[0876] NMR (CDCl₃) δ: 2.37 (3H, s), 6.19 (1H, s), 7.13 (1H, ddd, J=1.0Hz, 4.8 Hz, 7.4 Hz), 7.70-7.85 (3H, m), 7.93 (1H, d, J=8.4 Hz), 8.39(1H, d, J=1.8 Hz), 8.45 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 12.46 (1H,br s), hidden (1H).

[0877] Elementary Analysis: for C₁₇H₁₃F₃N₄O₂

[0878] Calcd.: C, 56.36; H, 3.62; N, 15.46.

[0879] Found: C, 56.56; H, 3.52; N, 15.63.

Reference Example 2-11

[0880] 2-Bromo-5-methoxybenzoic acid

[0881] The title compound was prepared according to the method describedin JP 63-287756 A. To a solution of 3-methoxybenzoic acid (25.0 g, 164mmol) in acetic acid (150 mL), a solution of bromine (26.5 g, 166 mmol)in acetic acid (75 mL) was added dropwise at room temperature, and themixture was stirred at the same temperature for 8 hours. The mixture waspoured into water, and the resulting crystals were collected byfiltration, washed with water, and air dried to give the title compound(29.5 g, 78% yield).

[0882] NMR (CDCl₃) δ: 3.84 (3H, s), 6.95 (1H, dd, J=3.0 Hz, 8.8 Hz),7.53 (1H, d, J=3.0 Hz), 7.58 (1H, d, J=8.8 Hz), hidden (1H).

Reference Example 2-12

[0883]5-Methoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0884] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2-bromo-5-methoxybenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (48% yield).

[0885] mp: 195-196° C. (recrystallized from ethanol).

[0886] NMR (DMSO-d₆) δ: 2.21 (3H, s), 3.77 (3H, s), 6.09 (1H, s), 7.17(1H, dd, J=3.2 Hz, 9.2 Hz), 7.29 (1H, ddd, J=1.0 Hz, 5.2 Hz, 7.4 Hz),7.44 (1H, d, J=3.2 Hz), 7.57 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=8.4 Hz),7.97 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.43 (1H, ddd, J=1.0 Hz, 1.8Hz, 5.2 Hz), 11.95 (1H, br s), hidden (1H).

[0887] Elementary Analysis: for C₁₇H₁₆N₄O₃

[0888] Calcd.: C, 62.95; H, 4.97; N, 17.27.

[0889] Found: C, 63.10; H, 5.17; N, 17.39.

Reference Example 2-13

[0890] 8-Methoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0891] Following the procedure described in Reference Example 2-1, thetitle compound was prepared from 2-amino-3-methoxybenzoic acid (92%yield).

[0892] mp: 177-180° C. (recrystallized from methanol/ethyl acetate).

[0893] Elementary Analysis: for C₁₂H₁₁NO₄

[0894] Calcd.: C, 61.80; H, 4.75; N, 6.01.

[0895] Found: C, 61.81; H, 4.72; N, 6.01.

Reference Example 2-14

[0896] 6,7-Dimethoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0897] Following the procedure described in Reference Example 2-1, thetitle compound was prepared from 2-amino-4,5-dimethoxybenzoic acid (65%yield).

[0898] mp: 200-202° C. (recrystallized from acetonitrile).

[0899] Elementary Analysis: for C₁₃H₁₃NO₅

[0900] Calcd.: C, 59.31; H, 4.98; N, 5.32.

[0901] Found: C, 59.28; H, 4.91; N, 5.56.

Reference Example 2-15

[0902]4,5-Dimethoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0903] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from6,7-dimethoxy-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinopyridine (64% yield).

[0904] NMR (DMSO-d₆) δ: 2.24 (3H, s), 3.75 (3H, s), 3.86 (3H, s), 6.27(1H, s), 7.14 (1H, s), 7.26-7.33 (1H, m), 7.41 (1H, s), 7.83 (1H, d,J=8.0 Hz), 7.97 (1H, dt, J=1.8 Hz, 8.4 Hz), 8.41-8.45 (1H, m), hidden(2H).

Reference Example 2-16

[0905] 6-(Methylsulfanyl)-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0906] Following the procedure described in Reference Example 2-1, thetitle compound was prepared from 2-amino-5-(methylsulfanyl)benzoic acid(68% yield).

[0907] mp: 137-140° C. (recrystallized from ethyl acetate/hexane).

[0908] Elementary Analysis: for C₁₂H₁₁NO₃S

[0909] Calcd.: C, 57.82; H, 4.45; N, 5.62.

[0910] Found: C, 57.80; H, 4.61; N, 5.48.

Reference Example 2-17

[0911]5-(Methylsulfanyl)-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0912] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from6-(methylsulfanyl)-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinopyridine (67% yield).

[0913] NMR (DMSO-d₆) δ: 2.24 (3H, s), 2.47 (3H, s), 6.21 (1H, s), 7.31(1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4 Hz), 7.48 (1H, dd, J=2.2 Hz, 8.8 Hz),7.60 (1H, d, J=8.8 Hz), 7.81-7.86 (2H, m), 7.98 (1H, ddd, J=1.8 Hz, 7.4Hz, 8.4 Hz), 8.44 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 12.18 (1H, s),hidden (1H).

Reference Example 2-18

[0914] 2-[[3-Methyl1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-5-nitrobenzoicacid

[0915] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2-bromo-5-nitrobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (96% yield).

[0916] mp: 270° C.

[0917] NMR (DMSO-d₆) δ: 2.28 (3H, s), 6.42 (1H, s), 7.32 (1H, ddd, J=0.8Hz, 4.8 Hz, 7.4 Hz), 7.63 (1H, d, J=9.4 Hz), 7.81 (1H, d, J=8.4 Hz),7.94-8.03 (1H, m), 8.22 (1H, dd, J=2.8 Hz, 9.4 Hz), 8.46-8.49 (1H, m),8.78 (1H, d, J=2.8 Hz), 13.20 (1H, br s), hidden (1H).

[0918] Elementary Analysis: for C₁₆H₁₃N₅O₄.0.75H₂O

[0919] Calcd.: C, 54.47; H, 4.14; N, 19.85.

[0920] Found: C, 54.49; H, 3.77; N, 19.79.

Reference Example 2-19

[0921]2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-4-nitrobenzoic acid

[0922] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2-chloro-4-nitrobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (86% yield).

[0923] mp: 270-271° C.

[0924] NMR (DMSO-d₆) δ: 2.28 (3H, s), 6.35 (1H, s), 7.30-7.35 (1H, m),7.66 (1H, dd, J=1.8 Hz, 8.4 Hz), 7.84 (1H, d, J=8.4 Hz), 7.95-8.04 (1H,m), 8.17 (1H, d, J=8.4 Hz), 8.28 (1H, d, J=1.8 Hz), 8.42-8.46 (1H, m),13.20 (1H, br s), hidden (1H).

[0925] Elementary Analysis: for C₁₆H₁₃N₅O₄.0.25H₂O

[0926] Calcd.: C, 55.90; H, 3.96; N, 20.37.

[0927] Found: C, 55.88; H, 4.00; N, 20.23.

Reference Example 2-20

[0928] Methyl 4-oxo-2-(2-oxopropyl)-4H-3,1-benzoxazine-5-carboxylate

[0929] To a solution of 2-methoxycarbonyl-6-nitrobenzoic acid (22.5 g,0.1 mol) in methanol (100 mL) was added 10% palladium-carbon (2.0 g, 50%hydrate), and the mixture was stirred at room temperature under hydrogenatmosphere for 1 hour. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure, and the residue wasdissolved in acetone (100 mL). To the solution was added dropwisediketene (23 mL, 0.30 mol) at room temperature. After the mixture wasstirred at room temperature for 16 hours, the solution was concentratedunder reduced pressure. The resulting crude crystals were collected byfiltration, washed with acetone and diethylether, and air dried (15.4g). The crude crystals were suspended in a mixture of acetic anhydride(10.4 mL, 0.11 mol) and tetrahydrofuran (60 mL), and the suspension washeated under reflux for 12 hours. The suspension was allowed to cool toroom temperature, and the solvents were evaporated under reducedpressure to give crude crystals. The crystals were collected byfiltration, washed with diethylether, and air dried to give the titlecompound (8.03 g, 31% yield).

[0930] NMR (CDCl₃) δ: 2.14 (2.25H, s), 2.35 (0.75H, s), 3.84 (0.5H, s),3.98 (2.25H, s), 4.00 (0.75H, s), 5.26 (0.75H, s), 7.32 (0.75H, dd,J=1.0 Hz, 7.4 Hz), 7.40 (0.75H, dd, J=1.0 Hz, 8.0 Hz), 7.53 (0.25H, dd,J=1.0 Hz, 7.4 Hz), 7.66 (0.25H, dd, J=1.0 Hz, 8.0 Hz), 7.69-7.88 (1H,m).

Reference Example 2-21

[0931] 2-Chloro-6-iodobenzoic acid

[0932] The title compound was prepared according to the method describedin Collection Czechoslov. Chem. Commn., vol.40, p.719 (1975). To anice-cold mixture of 2-amino-6-chlorobenzoic acid (10.0 g, 58.3 mmol) andconc. hydrochloric acid (50 mL), was added dropwise a solution of sodiumnitrite (4.42 g, 64.1 mmol) in water (10 mL). Furthermore, a solution ofpotassium iodide (14.5 g, 87.5 mmol) and conc. sulfuric acid (4 mL) inwater (30 mL) was added thereto at the same temperature, and the mixturewas heated to 100° C. and stirred for 2 hours. The reaction mixture wasallowed to cool to room temperature, poured into an aqueous sodiumthiosulfate solution, and organic matter was extracted with ethylacetate. The extract was washed with saturated brine and water and driedover anhydrous sulfuric acid, and the solvent was evaporated underreduced pressure. The resulting crude crystals were collected byfiltration, washed with hexane/diethylether, and air dried to give thetitle compound (12.1 g, 73% yield).

[0933] NMR (CDCl₃) δ: 7.20 (1H, dd, J=2.6 Hz, 8.8 Hz), 7.97 (1H, d,J=8.8 Hz), 7.99 (1H, d, J=2.6 Hz), hidden (1H).

Reference Example 2-22

[0934]6-Chloro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0935] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2-chloro-6-iodobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (28% yield).

[0936] mp: 201-202° C. (recrystallized from ethanol).

[0937] NMR (DMSO-d₆) δ: 2.22 (3H, s), 6.12 (1H, s), 7.10 (1H, dd, J=1.0Hz, 7.8 Hz), 7.32 (1H, ddd, J=1.0 Hz, 5.0 Hz, 7.0 Hz), 7.41 (1H, dd,J=7.4 Hz, 7.8 Hz), 7.52 (1H, dd, J=1.0 Hz, 8.4 Hz), 7.88 (1H, dd, J=1.0Hz, 7.4 Hz), 8.01 (1H, ddd, J=1.8 Hz, 7.0 Hz, 8.4 Hz), 8.42 (1H, ddd,J=0.8 Hz, 1.8 Hz, 5.0 Hz), 11.35 (1H, br s), hidden (1H).

[0938] Elementary Analysis: for C₁₆H₁₃ClN₄O₂

[0939] Calcd.: C, 58.45; H, 3.99; N, 17.04.

[0940] Found: C, 58.29; H, 4.07; N, 17.03.

Reference Example 2-23

[0941] 6-Chloro-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one

[0942] Following the procedure described in Reference Example 2-1, thetitle compound was prepared from 2-amino-5-chlorobenzoic acid (46%yield).

[0943] mp: 159-160° C. (recrystallized from acetonitrile).

[0944] Elementary Analysis: for C₁₁H₈ClNO₃

[0945] Calcd.: C, 57.82; H, 4.45; N, 5.62.

[0946] Found: C, 57.80; H, 4.61; N, 5.48.

Reference Example 2-24

[0947] 4-Chloro-2-iodobenzoic acid

[0948] Following the procedure described in Reference Example 2-21, thetitle compound was prepared from 2-amino-4-chlorobenzoic acid (28%yield).

[0949] NMR (CDl₃) δ: 7.44 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.98 (1H, d, J=8.4Hz), 8.08 (1H, d, J=2.2 Hz), hidden (1H).

Reference Example 2-25

[0950] 2,4,5-Trichlorobenzoic acid

[0951] The title compound was prepared according to the method describedin JP 7-165638 A. Aluminum chloride (53.3 g, 0.4 mol) was suspended incarbon tetrachloride (194 g, 2 mol) at 0° C., and the suspension wasgradually heated. 1,3,4-Trichlorobenzene (36.4 g, 0.2 mol) was addeddropwise over 2 hours under reflux, and the mixture was heated underreflux further for 0.5 hour. After the solution was allowed to cool toroom temperature, the mixture was carefully poured into iced water. Theorganic layer was washed with water, an aqueous 5% sodium bicarbonatesolution and water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give crude crystals of1,2,4-trichloro-5-(trichloromethyl)benzene (41.0 g, 69% yield) whichwere collected by filtration. The crude crystals (27.6 g, 92.4 mmol)were suspended in 95% sulfuric acid (90 mL), and the suspension wasstirred at 50° C. for 7 hours. The solution was poured into iced water,and the resulting crude crystals were collected by filtration. Thecrystals were dissolved in 1N sodium hydroxide, and the solution waswashed with ethyl acetate. The aqueous layer was neutralized with 6Nhydrochloric acid, and the organic matter was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The crude crystals thus obtained were collected by filtration, washedwith hexane, and air dried to give the title compound (17.6 g, 85%yield). NMR (CDCl₃) δ: 7.20 (1H, dd, J=2.6 Hz, 8.8 Hz), 7.97 (1H, d,J=8.8 Hz), 7.99 (1H, d, J=2.6 Hz), hidden (1H).

Reference Example 2-26

[0952]4,5-Dichloro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0953] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2,4,5-trichlorobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (92% yield).

[0954] mp: 288-289° C. (recrystallized from ethanol).

[0955] NMR (DMSO-d₆) δ: 2.26 (3H, s), 6.32 (1H, s), 7.29-7.35 (1H, m),7.69 (1H, s), 7.83 (1H, d, J=8.4 Hz), 7,94-8.03 (2H, m), 8.41-8.44 (1H,m), 12.34 (1H, br s), hidden (1H).

[0956] Elementary Analysis: for C₁₆H₁₂Cl₂N₄O₂

[0957] Calcd.: C, 52.91; H, 3.33; N, 15.43.

[0958] Found: C, 52.64; H, 3.20; N, 15.30.

Reference Example 2-27

[0959] 3,5-Dichloro-2-iodobenzoic acid

[0960] Following the procedure described in Reference Example 2-21, thetitle compound was prepared from 2-amino-3,5-dichlorobenzoic acid (88%yield).

[0961] NMR (CDCl₃) δ: 7.44 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.98 (1H, d,J=8.4 Hz), 8.08 (1H, d, J=2.2 Hz), hidden (1H).

Reference Example 2-28

[0962]3,5-Dichloro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[0963] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 3,5-dichloro-2-iodobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (16% yield).

[0964] mp: 288-289° C.

[0965] NMR (DMSO-d₆) δ: 2.12 (3H, s), 5.21 (1H, s), 7.28 (1H, t, J=5.4Hz), 7.83-7.94 (4H, m), 8.43 (1H, d, J=4.4 Hz), 10.66 (1H, br s), hidden(1H).

[0966] Elementary Analysis: for C₁₆H₂₁Cl₂N₄O₂

[0967] Calcd.: C, 52.91; H, 3.33; N, 15.43.

[0968] Found: C, 52.67; H, 3.25; N, 15.31.

Reference Example 2-29

[0969] 2-Amino-5-fluorobenzoic acid

[0970] Following the procedures described below in Reference Examples2-31 and 2-32, the title compound was prepared from5-fluoro-2-nitrotoluene (25% yield).

[0971] NMR (CDCl₃) δ: 5.94 (3H, br s), 6.64 (1H, dd, J=4.6 Hz, 9.0 Hz),7.04-7.15 (1H, m), 7.60 (1H, dd, J=3.0 Hz, 9.6 Hz).

Reference Example 2-30

[0972] 5-Fluoro-2-iodobenzoic acid

[0973] Following the procedure described in Reference Example 2-21, thetitle compound was prepared from 2-amino-5-fluorobenzoic acid (41%yield).

[0974] NMR (CDCl₃) δ: 6.99 (1H, ddd, J=3.0 Hz, 5.4 Hz, 8.8 Hz), 7.76(1H, dd, J=3.0 Hz, 8.8 Hz), 8.02 (1H, dd, J=5.4 Hz, 8.8 Hz), hidden(1H).

Reference Example 2-31

[0975] 4-Fluoro-2-nitrobenzoic acid

[0976] A mixture of 4-fluoro-2-nitrotoluene (25.0 g, 161 mmol),potassium permanganate (102 g, 645 mmol) and water (500 mL) was heatedand stirred at 100° C. for 3 hours. The solution was allowed to cool toroom temperature, filtered through Celite to remove the insolublederived from potassium permanganate. The filtrate was washed withdiethylether and made acidic by the addition of conc. hydrochloric acid,and organic matter was extracted with diethylether. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (10.1 g, 34% yield).

[0977] NMR (CDCl₃) δ: 7.40 (1H, ddd, J=2.6 Hz, 7.4 Hz, 8.8 Hz), 7.53(1H, dd, J=2.6 Hz, 7.6 Hz), 8.00 (1H, dd, J=5.6 Hz, 8.8 Hz), 8.52 (1H,br s).

Reference Example 2-32

[0978] 2-Amino-4-fluorobenzoic acid

[0979] To a solution of 4-fluoro-2-nitrobenzoic acid (22.5 g, 0.1 mol)in ethanol (200 mL), 10% palladium-carbon (1.0 g, 50% hydrate) wasadded, and the mixture was stirred at room temperature under hydrogenatmosphere for 4 hours. The solution was filtered to remove thecatalyst, and the filtrate was concentrated under reduced pressure togive the title compound (8.38 g, 100% yield).

[0980] NMR (CDCl₃) δ: 5.95 (2H, br s), 6.31-6.44 (2H, m), 7.93 (1H, dd,J=6.4 Hz, 8.6 Hz), hidden (1H).

Reference Example 2-33

[0981] 4-Fluoro-2-iodobenzoic acid

[0982] Following the procedure described in Reference Example 2-21, thetitle compound was prepared from 2-amino-4-fluorobenzoic acid (60%yield).

[0983] NMR (CDCl₃) δ: 7.17 (1H, ddd, J=2.6 Hz, 7.8 Hz, 8.8 Hz), 7.80(1H, dd, J=2.6 Hz, 8.4 Hz), 8.08 (1H, dd, J=5.8 Hz, 8.8 Hz), hidden(1H).

Reference Example 2-34

[0984]4-Fluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[0985] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 4-fluoro-2-iodobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (86% yield).

[0986] mp: 242-243° C. (recrystallized from ethanol).

[0987] NMR (DMSO-d₆) δ: 2.26 (3H, s), 6.35 (1H, s), 6.74 (1H, ddd, J=2.2Hz, 8.0 Hz, 8.8 Hz), 7.27-7.36 (2H, m), 7.83 (1H, ddd, J=0.6 Hz, 1.2 Hz,8.4 Hz), 7.95-8.06 (2H, m), 8.44 (1H, ddd, J=0.6 Hz, 1.8 Hz, 4.8 Hz),12.37 (1H, br s), hidden (1H).

[0988] Elementary Analysis: for C₁₆H₁₃FN₄O₂

[0989] Calcd.: C, 61.53; H, 4.20; N, 17.94.

[0990] Found: C, 61.42; H, 4.32; N, 17.98.

Reference Example 2-35

[0991] N-(2-Fluorophenyl)-2-(hydroxyimino)acetamide

[0992] The title compound was prepared according to the method describedin J. Heterocyclic Chem., vol.27, p.2151 (1990). To a solution ofchloral hydrate (44.2 g, 267 mmol) and sodium sulfate (304 g, 2.14 mol)in water (700 mL), was added a solution of 2-fluoroaniline (27.0 g, 243mmol) and conc. hydrochloric acid (70 mL) in water (140 mL) dropwise atroom temperature, and furthermore hydroxylamine hydrochloride (74.4 g,1.07 mol), and the resulting solution was heated under reflux for 10minutes. The solution was ice cooled and the resulting crystals werecollected by filtration and air dried to give the title compound (38.0g, 86% yield).

[0993] mp: 120° C. (recrystallized from ethyl acetate/hexane).

[0994] NMR (CDCl₃) δ: 7.06-7.21 (3H, m), 7.61 (1H, s), 8.30-8.39 (1H,m), 8.57 (2H, br s).

[0995] Elementary Analysis: for C₈H₇FN₂O₂

[0996] Calcd.: C, 52.75; H, 3.87; N, 15.38.

[0997] Found: C, 52.76; H, 3.81; N, 15.32.

Reference Example 2-36

[0998] 7-Fluoro-1H-indol-2,3-dione

[0999] A solution of N-(2-fluorophenyl)-2-(hydroxyimino)acetamide (35.0g, 192 mmol) in sulfuric acid (150 mL) was heated and stirred at 70° C.for 45 minutes. The solution was allowed to cool to room temperature andpoured into iced water, and organic matter was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The resulting crystals were collected by filtration togive the title compound (14.6 g, 46% yield).

[1000] mp: 195-196° C. (recrystallized from ethyl acetate/hexane).

[1001] NMR (CDCl₃) δ: 7.12 (1H, ddd, J=4.4 Hz, 7.4 Hz, 8.4 Hz), 7.38(1H, ddd, J=1.0 Hz, 8.4 Hz, 9.6 Hz), 7.47 (1H, ddd, J=1.0 Hz, 1.2 Hz,7.4 Hz), 8.33 (1H, br s).

[1002] Elementary Analysis: for C₈H₄FNO₂

[1003] Calcd.: C, 58.19; H, 2.44; N, 8.48; F, 11.51.

[1004] Found: C, 58.10; H, 2.56; N, 8.37; F, 11.35.

Reference Example 2-37

[1005] 2-Amino-3-fluorobenzoic acid

[1006] A solution of 7-fluoro-1H-indol-2,3-dione (13.0 g, 78.7 mmol) in10N sodium hydroxide (125 mL) was heated and stirred at 70° C. for 1hour. 30% Hydrogen peroxide (25 mL) was added dropwise over 20 minutesat the same temperature, and the mixture was heated and stirred at thesame temperature further for 1 hour. The solution was ice cooled, andconc. hydrochloric acid was added to the solution carefully until the pHof the solution became 4. Organic matter was extracted with ethylacetate, and the extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The crystals thus obtained were collected byfiltration to give the title compound (7.15 g, 59% yield).

[1007] NMR (CDCl₃) δ: 6.00 (2H, br s), 6.60 (1H, dt, J=5.2 Hz, 8.0 Hz),7.16 (1H, ddd, J=1.4 Hz, 8.0 Hz, 11.2 Hz), 7.72 (1H, td, J=1.4 Hz, 8.0Hz), hidden (1H).

Reference Example 2-38

[1008] 3-Fluoro-2-iodobenzoic acid

[1009] Following the procedure described in Reference Example 2-21, thetitle compound was prepared from 2-amino-3-fluorobenzoic acid (19%yield).

[1010] NMR (CDCl₃) δ: 7.26 (1H, ddd, J=1.6 Hz, 7.6 Hz, 8.2 Hz), 7.42(1H, ddd, J=5.6 Hz, 7.6 Hz. 8.2 Hz), 7.79 (1H, ddd, J=0.8 Hz, 1.6 Hz,7.6 Hz), hidden (1H).

Reference Example 2-39

[1011] 6-Bromo-2,3-difluorobenzoic acid

[1012] A solution of 1.6M butyllithium in hexane (60 mL, 96 mmol) wasdiluted with tetrahydrofuran (180 mL) under an argon atmosphere, andcooled to −78° C. To the solution, were added dropwise2,2,6,6-tetramethylpiperidine (16.2 g, 116 mmol) and subsequently4-bromo-1,2-difluorobenzene (15.4 g, 80 mmol), and the mixture wasstirred at the same temperature for 2 hours. The solution was carefullypoured onto crushed dry ice, and the mixture was allowed to warm to roomtemperature. The solution was concentrated under reduced pressure, andthe residue was poured into water. After the solution was washed withdiethylether, the aqueous layer was made acidic by the addition of 6Nhydrochloric acid, and organic matter was extracted withdichloromethane. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound (10.8 g, 57% yield).

[1013] NMR (CDCl₃) δ: 7.18 (1H, td, J=8.6 Hz, 9.2 Hz), 7.40 (1H, ddd,J=2.0 Hz, 4.2 Hz, 8.6 Hz), hidden (1H).

Reference Example 2-40

[1014] Methyl 6-bromo-2,3-difluorobenzoate

[1015] A solution of 6-bromo-2,3-difluorobenzoic acid (7.66 g, 32.3mmol), methyl iodide (10 mL, 160 mmol) and potassium carbonate (5.36 g,38.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at roomtemperature for 1 hour. The solution was poured into water, and organicmatter was extracted with ethyl acetate. The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give the title compound (8.11 g,100% yield).

[1016] NMR (CDCl₃) δ: 3.99 (3H, s), 7.07-7.21 (1H, m), 7.35 (1H, ddd,J=2.0 Hz, 4.2 Hz, 8.8 Hz), hidden (1H).

Reference Example 2-41

[1017] Methyl2,3-difluoro-6-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoate

[1018] A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.16g, 35.4 mmol), methyl 6-bromo-2,3-difluorobenzoate (8.11 g, 32.3 mmol),copper acetate (II) (0.49 g, 2.7 mmol) and potassium carbonate (4.46 g,323 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux for 1hour under an argon atmosphere, and the solution was allowed to cool toroom temperature and poured into water. The solution was made weaklyacidic by the addition of acetic acid, and organic matter was extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (hexane:ethyl acetate=10:1 to 5:1) to give thetitle compound (0.86 g, 8% yield).

[1019] NMR (CDCl₃) δ: 2.30 (3H, s), 4.00 (3H, s), 5.94 (1H, s),7.11-7.27 (2H, m), 7.23 (1H, dd, J=8.2 Hz, 9.2 Hz), 7.80 (1H, ddd, J=1.8Hz, 7.4 Hz, 8.4 Hz), 7.94 (1H, ddd, J=1.0 Hz, 1.2 Hz, 8.4 Hz), 8.50 (1H,ddd, J=1.0 Hz, 1.8 Hz, 5.0 Hz), 11.60 (1H, br s).

[1020] Elementary Analysis: for C₁₇H₁₄F₂N₄O₂

[1021] Calcd.: C, 59.30; H, 4.10; N, 16.27; F, 11.04.

[1022] Found: C, 59.23; H, 4.22; N, 16.01; F, 10.86.

Reference Example 2-42

[1023]2,3-Difluoro-6-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[1024] To a solution of methyl2,3-difluoro-6-[[3-methyl1-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoate(0.80 g, 2.3 mmol) in methanol (40 mL) was added 1N sodium hydroxide (5mL) , and the mixture was heated under reflux for 2 hours. The solutionwas allowed to cool to room temperature, and concentrated under reducedpressure, and the residue was poured into water. The solution was madeweakly acidic by the addition of acetic acid, and the resulting crudecrystals were collected by filtration, washed with water, and air driedto give the title compound (0.64 g, 84% yield).

[1025] NMR (DMSO-d₆) δ: 2.22 (3H, s), 6.12 (1H, s), 7.32 (1H, ddd, J=1.2Hz, 4.8 Hz, 7.2 Hz), 7.37 (1H, ddd, J=1.8 Hz, 4.2 Hz, 9.6 Hz), 7.53 (1H,dd, J=9.6 Hz, 18.4 Hz), 7.86 (1H, br d, J=8.4 Hz), 7.99 (1H, ddd, J=1.8Hz, 7.2 Hz, 8.4 Hz), 8.43 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 11.64(1H, br s), hidden (1H).

Reference Example 2-43

[1026]4,5-Difluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[1027] Under an argon atmosphere, a solution of3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.01 g, 34.5 mmol),2-chloro-4,5-difluorobenzoic acid (6.64 g, 34.5 mmol), copper acetate(II) (0.718 g, 3.95 mmol) and potassium carbonate (4.77 g, 34.5 mmol) inN,N-dimethylformamide (30 mL) was heated under reflux for 2 hours. Thesolution was cooled to room temperature, and poured into water. Thesolution was made weakly acidic by the addition of acetic acid, and theresulting crude crystals were collected by filtration. The crystals werewashed with water and air dried to give the title compound (9.21 g, 81%yield).

[1028] mp: 247-248° C. (recrystallized from methanol).

[1029] NMR (DMSO-d₆) δ: 2.25 (3H, s), 6.33 (1H, s), 7.28-7.34 (1H, m),7.46-7.56 (1H, m), 7.80-8.02 (3H, m), 8.30-8.44 (1H, m), 12.30 (1H, brs), hidden (1H).

[1030] Elementary Analysis: for C₁₆H₁₂F₂N₄O₂

[1031] Calcd.: C, 58.18; H, 3.66; N, 16.96.

[1032] Found: C, 58.0.9; H, 3.48; N, 16.88.

Reference Example 2-44

[1033] 2,4-Dichloro-5-fluorobenzoic acid

[1034] Following the procedure described in Reference Example 2-25, thetitle compound was prepared from 2,4-dichloro-1-fluorobenzene (66%yield).

[1035] NMR (CDCl₃) δ: 7.59 (1H, d, J=6.2 Hz), 7.85 (1H, d, J=8.8 Hz),8.28 (1H, br s).

Reference Example 2-45

[1036]4-Chloro-5-fluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[1037] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2,4-dichloro-5-fluorobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (24% yield).

[1038] mp: 245-246° C. (recrystallized from ethyl acetate).

[1039] NMR (DMSO-d₆) δ: 2.25 (3H, s), 6.28 (1H, s), 7.28-7.35 (1H, m),7.64 (1H, d, J=6.6 Hz), 7.80-7.85 (2H, m), 7.95-8.03 (1H, m), 8.42 (1H,dd, J=1.2 Hz, 4.8 Hz), 12.21 (1H, br s), hidden (1H).

[1040] Elementary Analysis: for C₁₆H₁₂ClFN₄O₂

[1041] Calcd.: C, 55.42; H, 3.49; N, 16.16.

[1042] Found: C, 55.39; H, 3.43; N, 16.09.

Reference Example 2-46

[1043] 2,5-Dichloro-4-fluorobenzoic acid

[1044] Following the procedure described in Reference Example 2-25, thetitle compound was prepared from 1,4-dichloro-2-fluorobenzene (68%yield).

[1045] NMR (CDCl₃) δ: 7.33 (1H, d, J=8.8 Hz), 7.45 (1H, br s), 8.15 (1H,d, J=7.6 Hz).

Reference Example 2-47

[1046]5-Chloro-4-fluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[1047] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2,5-dichloro-4-fluorobenzoic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (95% yield).

[1048] mp: 250-252 ° C. (recrystallized from ethanol).

[1049] NMR (DMSO-d₆) δ: 2.26 (3H, s), 6.38 (1H, s), 7.32 (1H, ddd, J=1.2Hz, 4.8 Hz, 7.4 Hz), 7.49 (1H, d, J=12.4 Hz), 7.83 (1H, ddd, J=0.8 Hz,1.2 Hz, 8.4 Hz), 7.99 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.03 (1H, d,J=8.8 Hz), 8.42 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 12.41 (1H, br s),hidden (1H).

[1050] Elementary Analysis: for C₁₆H₁₂ClFN₄O₂

[1051] Calcd.: C, 55.42; H, 3.49; N, 16.16.

[1052] Found: C, 55.37; H, 3.44; N, 16.20.

Reference Example 2-48

[1053] 2-Chloro-6-hydrazinopyridine

[1054] The title compound was prepared according to the method describedin U.S. Pat. No. 4,260,767 (1981). A mixture of 2,6-dichloropyridine(25.0 g, 169 mmol) and hydrazine monohydrate (60 mL, 1.24 mol) washeated and stirred at 100° C. for 4 hours. The solution was ice cooled,and the resulting crude crystals were collected by filtration. Thecrystals were washed with cold water and air dried. The crystals thusobtained were recrystallized from chloroform/hexane to give the titlecompound (15.8 g, 65% yield).

[1055] NMR (CDCl₃) δ: 4.17 (2H, br s), 6.52 (1H, d, J=7.4 Hz), 6.65 (1H,d, J=8.0 Hz), 7.45 (1H, dd, J=7.4 Hz, 8.0 Hz), 7.82 (1H, br s).

Reference Example 2-49

[1056]2-[[1-(6-Chloropyridine-2-yl)-3-methyl-1H-pyrazol-5-yl]amino]benzoicacid

[1057] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from 2-(2-oxypropyl)-4H-3,1-benzoxazin-4-oneand 2-chloro-6-hydrazinopyridine (79% yield).

[1058] NMR (DMSO-d₆) δ: 2.23 (3H, s), 6.21 (1H, s), 6.92-7.00 (1H, m),7.35-7.38 (1H, m), 7.42-7.59 (2H, m), 7.80-7.88 (1H, m), 7.94-7.98 (1H,m), 8.03 (1H, d, J=8.0 Hz), 11.26 (1H, br s), hidden (1H).

Reference Example 2-50

[1059] 5-Chloro-2-hydrazinopyridine

[1060] Following the procedure described in Reference Example 2-48, thetitle compound was prepared from 2,5-dichloropyridine and hydrazinehydrate (51% yield).

[1061] NMR (CDCl₃) δ: 4.13 (2H, br s), 6.73 (1H, d, J=8.8 Hz), 7.49 (1H,dd, J=2.6 Hz, 8.8 Hz), 7.61 (1H, br s), 7.96 (1H, d, J=2.6 Hz).

Reference Example 2-51

[1062]2-[[1-(5-Chloropyridin-2-yl)-3-methyl-1H-pyrazol-5-yl]amino]benzoic acid

[1063] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from 2-(2-oxypropyl)-4H-3,1-benzoxazin-4-oneand 5-chloro-2-hydrazinopyridine (63% yield).

[1064] NMR (DMSO-d₆) δ: 2.24 (3H, s), 6.26 (1H, s), 6.92-7.00 (1H, m),7.49-7.63 (2H, m), 7.87 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=7.6 Hz), 8.09(1H, dd, J=2.4 Hz, 8.8 Hz), 8.42 (1H, d, J=2.4 Hz), 12.03 (1H, br s),hidden (1H).

Reference Example 2-52

[1065] 2-Hydrazino-3-methylpyridine

[1066] Following the procedure described in Reference Example 2-48, thetitle compound was prepared from 2-bromo-3-methylpyridine and hydrazinemonohydrate (60% yield).

[1067] NMR (DMSO-d₆) δ: 2.03 (3H, s), 4.10 (2H, br s), 6.53 (1H, dd,J=5.2 Hz, 7.4 Hz), 7.09 (1H, br s), 7.23 (1H, dd, J=1.0 Hz, 7.4 Hz),7.94 (1H, dd, J=1.0 Hz, 5.2 Hz).

Reference Example 2-53

[1068] 3-Hydrazinopyridine dihydrochloride

[1069] To a mixture of 3-aminopyridine (9.41 g, 100 mmol) and conc.hydrochloric acid (100 mL) which was cooled to a temperature of lowerthan −5° C., a solution of sodium nitrite (7.20 g, 105 mmol) in water(60 mL) was added dropwise. Subsequently, a solution of tin chloride(II) (56.9 g, 300 mmol) in conc. hydrochloric acid (50 mL) was addeddropwise thereto carefully so that the temperature of the solution didnot exceed −5° C. The solution was stirred at a temperature of lowerthan −5° C. for additional 3 hours, and the resulting crystals werecollected by filtration. The crystals were washed withdiethylether/methanol and air dried to give the title compound (15.6 g,85% yield). The compound was used in the following process withoutfurther purification.

Reference Example 2-54

[1070] 2-[[3-Methyl-1-(3-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[1071] A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (10.2 g,50.0 mmol), 3-hydrazinopyridine dihydrochloride (9.10 g, 50.0 mmol) andsodium acetate (9.84 g, 120 mmol) in ethanol (100 mL) was heated underreflux for 1 hour. The solution was cooled to room temperature andconcentrated under reduced pressure. The residue was poured into water,and organic matter was extracted with a mixture of chloroform/methanol.The extract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvents were evaporated under reducedpressure. The residue thus obtained was crystallized from ethylacetate/diethylether/hexane to give the title compound (10.1 g, 69%yield).

[1072] NMR (DMSO-d₆) δ: 2.27 (3H, s), 6.27 (1H, s), 6.77-6.84 (1H, m),6.91 (1H, d, J=8.2 Hz), 7.38 (1H, t, J=7.6 Hz), 7.45-7.52 (1H, m), 7.88(1H, d, J=7.6 Hz), 7.97 (1H, d, J=7.6 Hz), 8.50-8.53 (1H, m), 8.79 (1H,s), 9.94 (1H, br s), hidden (1H).

Reference Example 2-55

[1073] 4-Hydrazinopyridine hydrochloride

[1074] The title compound was prepared according to the method describedin J. Chem. Soc., p.3830 (1959). A solution of 4-chloropyridine (16.5 g,145 mmol) and hydrazine monohydrate (7.76 mL, 160 mmol) in 1-propanol(50 mL) was heated under reflux for 18 hours. The solution was cooled to0° C., and the resulting crystals were collected by filtration. Thecrystals were washed with cold 1-propanol and air dried to give thetitle compound (15.2 g, 72% yield). The compound was used in thefollowing process without further purification.

Reference Example 2-56

[1075] 2-[[3-Methyl-1-(4-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[1076] A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (16.7 g,82.4 mmol), 4-hydrazinopyridine hydrochloride (12.0 g, 82.4 mmol) andsodium acetate (8.10 g, 98.9 mmol) in ethanol (300 mL) was heated underreflux for 30 minutes. The solution was cooled to room temperature andconcentrated under reduced pressure. The residue was poured into waterand the resulting crude crystals were collected by filtration. Thecrystals were washed with ethanol and air dried to give the titlecompound (11.9 g, 49% yield).

[1077] NMR (DMSO-d₆) δ: 2.27 (3H, s), 6.31 (1H, s), 6.80-6.91 (2H, m),7.35-7.39 (1H, m), 7.65 (2H, d, J=6.2 Hz), 7.91 (1H, d, J=8.2 Hz), 8.58(2H, d, J=6.2 Hz), 10.28 (1H, br s), hidden (1H).

Reference Example 2-57

[1078] 2-Hydrazinopyrimidine

[1079] The title compound was prepared according to the method describedin Yakugaku Zasshi, vol.73, p.598 (1953). A mixture of2-chloropyrimidine (25.0 g, 218 mmol), potassium carbonate (25.0 g, 181mmol), and hydrazine monohydrate (50 mL, 1.01 mol) was heated andstirred at 100° C. for 20 minutes. The mixture was ice cooled and theresulting crude crystals were collected by filtration. The crystals werewashed with cold water, air dried, and recrystallized from benzene togive the title compound (19.7 g, 82% yield).

[1080] NMR (DMSO-d₆) δ: 4.12 (2H, br s), 6.60 (1H, t, J=4.8 Hz), 8.10(1H, br s), 8.31 (2H, d, J=4.8 Hz).

Reference Example 2-58

[1081] 2-[[3-Methyl-1-(4,6-dimethyl-2-pyrimidinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[1082] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from 2-(2-oxypropyl)-4H-3,1-benzoxazin-4-oneand 2-hydrazino-4,6-dimethylpyrimidine (91% yield).

[1083] mp: 142-143° C. (recrystallized from ethyl acetate/methanol). NMR(CDCl₃) δ: 2.37 (3H, s), 2.54 (6H, s), 6.12 (1H, s), 6.81 (1H, s), 6.93(1H, dd, J=1.0 Hz, 8.0 Hz), 7.49 (1H, ddd, J=1.6 Hz, 8.0 Hz, 8.6 Hz),7.67 (1H, dd, J=1.0 Hz, 8.6 Hz), 8.09 (1H, dd, J=1.6 Hz, 8.0 Hz), 11.54(1H, dd, J=1.0 Hz, 8.6 Hz), hidden (1H).

Reference Example 2-59

[1084] 2-Hydrazinothiazole hydrochloride

[1085] The title compound was prepared according to the method describedin Can. J. Chem., vol.48, p.3554 (1970). To a mixture of 2-aminothiazole(10.0 g, 100 mmol) and conc. hydrochloric acid (80 mL) cooled to atemperature of below −10° C., a solution of sodium nitrite (6.90 g, 100mmol) in water (50 mL) was added dropwise. Furthermore, a solution oftin chloride (II) (37.9 g, 200 mmol) in conc. hydrochloric acid (20 mL)was added dropwise carefully so that the temperature of the solution didnot exceed −10° C. After the addition, the resulting crystals werecollected by filtration. The crystals were recrystallized fromdiethylether/methanol to give the title compound (9.22 g, 61% yield)

[1086] NMR (DMSO-d₆) δ: 3.49 (3H, br s), 7.02 (1H, d, J=4.0 Hz), 7.29(1H, d, J=4.0 Hz).

Reference Example 2-60

[1087] 2-[[3-Methyl-1-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]amino]benzoicacid

[1088] Following the procedure described in Reference Example 2-3, thetitle compound was prepared from 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-oneand 2-hydrazinothiazole hydrochloride (46% yield)

[1089] NMR (DMSO-d₆) δ: 2.22 (3H, s), 6.24 (1H, s), 6.97-7.05 (1H, m),7.47 (1H, d, J=3.8 Hz), 7.57-7.64 (3H, m), 7.97 (1H, dd, J=1.4 Hz, 7.6Hz), 11.59 (1H, br s), hidden (1H).

Reference Example 2-61

[1090] Methyl3-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-thiphenecarboxylate

[1091] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from methyl 3-iodo-2-thiphenecarboxylate and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (40% yield).

[1092] mp: 140-141° C.

[1093] NMR (CDCl₃) δ: 2.32 (3H, s), 3.93 (3H, s), 5.95 (1H, s),7.11-7.18 (1H, m), 7.30 (1H, d, J=5.6 Hz), 7.45 (1H, d, J=5.6 Hz),7.75-7.83 (1H, m), 7.93 (1H, dd, J=1.2 Hz, 8.4 Hz), 8.53-8.57 (1H, m),hidden (1H).

[1094] Elementary Analysis: for C₁₅H₁₄N₄O₂S

[1095] Calcd.: C, 57.31; H, 4.49; N, 17.82.

[1096] Found: C, 57.40; H, 4.61; N, 17.85.

Reference Example 2-62

[1097]3-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-thiophenecarboxylicacid

[1098] Following the procedure described in Reference Example 2-42, thetitle compound was prepared from methyl3-[[3-methyl-1-(2-pyridinyl)-1H-pyrazole-5-yl]amino]-2-thiophenecarboxylicacid (47% yield).

[1099] mp: 169-170° C. (recrystallized from methanol).

[1100] NMR (DMSO-d₆) δ: 2.24 (3H, s), 6.18 (1H, s), 7.27-7.33 (1H, m),7.41 (1H, d, J=5.4 Hz), 7.82-7.87 (2H, m), 7.94-8.02 (1H, m), 8.43 (1H,dd, J=1.0 Hz, 5.1 Hz), 12.31 (1H, br s), hidden (1H).

[1101] Elementary Analysis: for C₁₄H₁₂N₄O₂S

[1102] Calcd.: C, 55.99; H, 4.03; N, 18.65.

[1103] Found: C, 55.92; H, 4.03; N, 18.62.

Reference Example 2-63

[1104] Ethyl 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate

[1105] A solution of ethyl 2-(ethoxymethylene)-2-cyanoacetate (33.8 g,200 mmol) and 2-hydrazinopyridine (21.8 g, 200 mmol) in ethanol (100 mL)was heated under reflux for 20 minutes. The solution was cooled to roomtemperature, and the resulting crystals were collected by filtration.The crystals were washed with ethanol and air dried to give the titlecompound (33.8 g, 73% yield).

[1106] mp: 103-104° C. (recrystallized from ethyl acetate). NMR (CDCl₃)δ: 1.37 (3H, t, J=7.0 Hz), 4.31 (2H, q, J=7.0 Hz), 7.12-7.18 (1H, m),7.48 (2H, br s), 7.76 (1H, s), 7.77-7.87 (1H, m), 7.95 (1H, d, J=8.4Hz), 8.35-8.38 (1H, m).

Reference Example 2-64

[1107] 1-(2-Pyridinyl)-1H-pyrazol-5-ylamine

[1108] A suspension of ethyl5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate (27.9 g, 120 mmol) in4N sodium hydroxide (300 mL) was heated under reflux for 1 hour. Thesuspension was allowed to cool to room temperature, neutralized by theaddition of conc. hydrochloric acid, and further made acidic by theaddition of acetic acid. The resulting crystals were collected byfiltration, washed with ethanol, and air dried. The crystals thusobtained were subjected to heat at 200° C., and washed with diethyletherto give the title compound (6.02 g, 31% yield). NMR (CDCl₃) δ: 5.51 (1H,d, J=1.8 Hz), 5.95 (2H, br s), 7.07-7.13 (1H, m), 7.42 (1H, d, J=1.8Hz), 7.75-7.84 (1H, m), 7.98 (1H, d, J=8.4 Hz), 8.33 (1H, dd, J=1.6 Hz,4.6 Hz).

Reference Example 2-65

[1109] 2-[[I-(2-Pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[1110] A solution of 1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.02 g, 37.6mmol), 2-iodobenzoic acid (9.32 g, 37.6 mmol), copper acetate (II)(0.683 g, 3.76 mmol) and potassium carbonate (5.72 g, 41.4 mmol) inN,N-dimethylformamide (20 mL) was heated under reflux for 1 hour underan argon atmosphere. The solution was allowed to cool to roomtemperature, and poured into water. The solution was made weakly acidicby the addition of acetic acid, and the resulting crude crystals werecollected by filtration. The crystals were washed with water and airdried to give the title compound (9.45 g, 90% yield).

[1111] mp: 216-218° C. (recrystallized from ethanol).

[1112] NMR (DMSO-d₆) δ: 6.40 (1H, d, J=2.2 Hz), 6.90-6.98 (1H, m), 7.37(1H, ddd, J=1.2 Hz, 5.0 Hz, 7.2 Hz), 7.48-7.57 (1H, m), 7.61 (1H, dd,J=1.0 Hz, 8.4 Hz), 7.69 (1H, d, J=2.2 Hz), 7.88-8.08 (3H, m), 8.49 (1H,dd, J=1.0 Hz, 5.0 Hz), 12.20 (1H, br s), hidden (1H).

[1113] Elementary Analysis: for C₁₅H₁₂N₄O₂

[1114] Calcd.: C, 64.28; H, 4.32; N, 19.99.

[1115] Found: C, 64.44; H, 4.26; N, 20.11.

Reference Example 2-66

[1116] 5-Chloro-2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid

[1117] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 5-chloro-2-iodobenzoic acid and1-(2-pyridinyl)-1H-pyrazol-5-ylamine (88% yield).

[1118] mp: 233-234° C. (recrystallized from ethanol).

[1119] NMR (DMSO-d₆) δ: 6.42 (1H, d, J=2.0 Hz), 7.38 (1H, ddd, J=1.2 Hz,4.8 Hz, 7.4 Hz), 7.54 (1H, dd, J=2.6 Hz, 8.8 Hz), 7.63 (1H, d, J=8.8Hz), 7.71 (1H, d, J=2.0 Hz), 7.88-7.92 (2H, m), 7.99-8.08 (1H, m), 8.47(1H, dd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 12.24 (1H, br s), hidden (1H).

[1120] Elementary Analysis: for C₁₅H₁₁ClN₄O₂

[1121] Calcd.: C, 57.24; H, 3.52; N, 17.80.

[1122] Found: C, 57.13; H, 3.46; N, 17.72.

Reference Example 2-67

[1123] 1-(2-Pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylamine

[1124] To diisopropylamine (32 mL, 0.23 mol), a solution of 1.6 Mbutyllithium in hexane (148 mL, 0.23 mol) was added dropwise at −78° C.under a dry nitrogen atmosphere. Furthermore, a solution of acetonitrile(8.2 g, 0.20 mol) and methyl trifluoroacetate (12.8 g, 0.10 mol) intetrahydrofuran (100 mL) was added dropwise thereto. After addition, thesolution was stirred while the solution was allowed to warm gradually to0° C. Iced water was added to the reaction solution, and the reactionsolution was concentrated under reduced pressure. After the residue (anaqueous solution) was extracted with diethylether, pH of the solutionwas adjusted to about 1 to 2 by the addition of conc. hydrochloric acid.The solution was washed with dichloromethane, and subsequently extractedwith diethylether. The extract was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give an oil. A solutionof the oil thus obtained (5.04 g, 32.5 mmol) and 2-hydrazinopyridine(3.91 g, 35.8 mmol) in dichloroethane (100 mL) was heated under refluxfor 8 hours. The solution was cooled to room temperature, and thesolvent was evaporated under reduced pressure. The residue thus obtainedwas dissolved in methanol (100 mL). To the mixture was added 28% sodiummethoxide (0.65 mL, 3.2 mmol) and the mixture was stirred at roomtemperature for 20 hours. The solution was concentrated under reducedpressure, water was added to the residue, and the organic matter wasextracted with chloroform. The extract was washed with saturated brineand dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (hexane:ethyl acetate=3:1to 2:1) to give the title compound (0.40 g, 7% yield).

[1125] NMR (CDCl₃) δ: 5.75 (1H, s), 6.09 (2H, br s), 7.16-7.22 (1H, m),8.01-8.05 (1H, m), 8.35-8.39 (1H, m).

[1126] Elementary Analysis: for C₉H₇F₃N₄

[1127] Calcd.: C, 47.37; H, 3.09; N, 24.55; F, 24.98.

[1128] Found: C, 47.35; H, 2.90; N, 24.63; F, 25.09.

Reference Example 2-68

[1129] 2-(2-Oxobutyl)-4H-3,1-benzoxazin-4-one

[1130] To a solution in a mixture of benzene (100 mL)/acetone (100 mL)of the crude 5-(2-hydroxybutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dionewhich was previously prepared from Meldrum's acid (57.7 g, 0.40 mol) andpropionyl chloride(37.0 g, 0.40 mol) according to the methods describedin Synthesis, p.1213 (1992) and Org. Synth., vol.63, p.198 (1985),anthranilic acid (45.8 g, 0.33 mol) was added and the mixture was heatedunder reflux for 3 hours. The solution was cooled to room temperatureand concentrated under reduced pressure. The residue was suspended in amixture of acetic anhydride (68.1 g, 0.667 mol) and tetrahydrofuran (150mL), and the suspension was heated under reflux for 30 minutes. Thesolution was cooled to room temperature and concentrated under reducedpressure, and the residue thus obtained was purified by silica gelcolumn chromatography (ethyl acetate:hexane=2:8) to give the titlecompound (28.4 g, 33% yield).

[1131] mp: 70-72° C. (recrystallized from hexane). Elementary Analysis:for C₁₂H₁₁NO₃

[1132] Calcd.: C, 66.35; H, 5.10; N, 6.45.

[1133] Found: C, 66.24; H, 5.16; N, 6.49.

Reference Example 2-69

[1134]5-Amino-3-(cyanomethyl)-1-(2-pyridinyl)-1H-pyrazole-4-carbonitrile

[1135] A solution of malononitrile (19.8 g, 300 mmol) and2-hydrazinopyridine (16.4 g, 150 mmol) in ethanol (300 mL) was heatedunder reflux for 12 hours. The solution was cooled to room temperature,and the resulting crystals were collected by filtration. The crystalswere purified by silica gel column chromatography (chloroform to 2%methanol/chloroform) to give the title compound (12.5 g, 37% yield).

[1136] mp: 178-179° C. (recrystallized from ethanol).

[1137] NMR (CDCl₃) δ: 3.78 (2H, s), 7.00 (2H, br s), 7.20-7.27 (1H, m),7.83-7.92 (1H, m), 7.96-8.00 (1H, m), 8.36-8.39 (1H, m).

[1138] Elementary Analysis: for C₁₁H₈N₆.0.1H₂O

[1139] Calcd.: C, 58.45; H, 3.66; N, 37.18.

[1140] Found: C, 58.58; H, 3.53; N, 36.90.

Reference Example 2-70

[1141] Methyl 2-[5-amino-1-(2-pyridinyl)-1H-pyrazol-3-yl]acetate

[1142] A solution of5-amino-3-(cyanomethyl)-1-(2-pyridinyl)-1H-pyrazole-4-carbonitrile (2.24g, 10 mmol) in 7.5N sodium hydroxide (20 mL) was heated under reflux for12 hours. The solution was cooled to room temperature, and diluted withwater. The solution was made acidic by the addition of 6N hydrochloricacid, and the resulting crystals were collected by filtration. To asuspension of the crystals in methanol (60 mL), conc. sulfuric acid (1mL) was added carefully, and the mixture was heated under reflux for 16hours. The solution was cooled to room temperature and diluted withwater. The solution was made basic by the addition of an aqueoussaturated sodium bicarbonate solution, and extracted with chloroform.The extract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto give the title compound (1.73 g, 75% yield).

[1143] mp: 84-85° C. (recrystallized from ethanol). NMR (CDCl₃) δ: 3.63(3H, s), 3.73 (3H, s), 5.52 (1H, s), 5.94 (2H, br s), 7.08 (1H, ddd,J=1.2 Hz, 5.2 Hz, 7.4 Hz), 7.77 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz),7.94 (1H, td, J=1.2 Hz, 8.4 Hz), 8.31 (1H, ddd, J=1.0 Hz, 1.8 Hz, 5.2Hz).

[1144] Elementary Analysis: for C₁₁H₈N₆.0.1H₂O

[1145] Calcd.: C, 56.89; H, 5.21; N, 24.12.

[1146] Found: C, 56.94; H, 5.22; N, 24.05.

Reference Example 2-71

[1147] Ethyl 5-amino-1-(2-pyridinyl)-1H-pyrazole-3-carboxylate

[1148] To diethyl ether (200 mL), was added a 20% sodium ethoxideethanol solution (280 g, 820 mmol) at 0° C., and subsequently was addeddropwise diethyl oxalate (19.8 g, 400 mmol), and the mixture was stirredat the same temperature for 30 minutes. To the solution, was addeddropwise a solution of acetonitrile (21 mL, 400 mmol) in diethylether(20 mL), and the mixture was allowed to warm to room temperature andstirred at the same temperature for 24 hours. The resulting crystalswere collected by filtration. The crystals were suspended in chloroform(400 mL), to which a solution of 2-hydrazinopyridine (34.3 g, 314 mmol)and conc. sulfuric acid (16.7 mL, 314 mmol) in water (300 mL) was addeddropwise at room temperature, and the mixture was stirred at the sametemperature for 72 hours. The organic layer was separated and theaqueous layer was extracted with chloroform. The organic layers werecombined, washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(hexane:ethyl acetate=3:1 to 1:1) to give the title compound (30.0 g,45% yield).

[1149] NMR (CDCl₃) δ: 1.41 (3H, t, J=7.0 Hz), 4.41 (2H, q, J=7.0 Hz),7.18 (1H, ddd, J=1.0 Hz, 5.2 Hz, 7.4 Hz), 7.84 (1H, ddd, J=1.8 Hz, 7.4Hz, 8.4 Hz), 8.13 (1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz), 8.37 (1H, ddd,J=0.8 Hz, 1.8 Hz, 5.2 Hz).

[1150] Elementary Analysis: for C₁₁H₁₂N₄O₂

[1151] Calcd.: C, 56.89; H, 5.21; N, 24.12.

[1152] Found: C, 56.80; H, 5.17; N, 23.94.

Reference Example 2-72

[1153] 3-(4-Methoxyphenyl)-1-(2-pyridinyl)-1H-pyrazol-5-ylamine

[1154] Following the procedure described in Reference Example 2-4, thetitle compound was prepared from 2-hydrazinopyridine and3-(4-methoxyphenyl)-3-oxypropanenitrile prepared from tert-butylcyanoacetate and 4-methoxybenzoyl chloride according to the methoddescribed in Synthesis, p.337 (1997) (3.48 g, 95% yield). NMR (CDCl₃) δ;3.85 (3H, s), 5.80 (1H, s), 5.99 (2H, br s), 6,94 (2H, ddd, J=1.2 Hz,3.0 Hz, 8.8 Hz), 7.08 (1H, ddd, J=1.0 Hz, 5.0 Hz, 7.2 Hz), 7.75-7.84(3H, m), 8.11 (1H, td, J=1.0 Hz, 8.4 Hz), 8.33 (1H, ddd, J=1.0 Hz, 1.8Hz, 5.0 Hz).

Reference Example 2-73

[1155] 2-[[3-Methyl-1-(3-pyridinylmethyl)-1H-pyrazol-5-yl]amino]benzoicacid

[1156] A solution in ethanol (50 mL) of2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (11.2 g, 55.1 mmol) and3-hydrazinomethylpyridine (7.44 g, 60.4 mmol) which was prepared from3-chloromethylpyridine following the method described in ReferenceExample 2-2, was heated under reflux for 1 hour. The solution was cooledto room temperature, and the resulting crude crystals were collected byfiltration. The crystals were washed with ethanol and air dried to givethe title compound (11.3 g, 67% yield). mp: 180-183° C. (recrystallizedfrom ethanol). NMR (DMSO-d₆) δ: 2.18 (3H, s), 5.18 (2H, s), 6.05 (1H,s), 6.75-6.92 (2H, m), 7.28-7.44 (2H, m), 7.49-7.58 (1H, m), 7.89 (1H,dd, J=1.5 Hz, 8.1 Hz), 8.40 (1H, s), 8.46 (1H, dd, J=1.5 Hz, 4.8 Hz),9.66 (1H, br s).

[1157] Elementary Analysis: for C₁₇H₁₆N₄O₂

[1158] Calcd.: C, 66.22; H, 5.23; N, 18.17.

[1159] Found: C, 66.02; H, 5,09; N, 18.30.

Reference Example 2-74

[1160] 2-[[3-Methyl-1-(4-pyridinylmethyl)-1H-pyrazol-5-yl]amino]benzoicacid

[1161] An ethanol (50 mL) solution of2-(2-oxypropyl)-4H-3,1-benzoxazin-4-one (9.04 g, 44.5 mmol) and4-hydrazinomethylpyridine (6.03 g, 49 mmol) which was previouslyprepared from 4-chloromethylpyridine following the method described inReference Example 2-2, was heated under reflux for 1 hour. The solutionwas cooled to room temperature, and the resulting crude crystals werecollected by filtration. The crystals were washed with ethanol and airdried to give the title compound (7.66 g, 56% yield).

[1162] mp: 235-238° C. (recrystallized from ethanol).

[1163] Elementary Analysis: for C₁₇H₁₆N₄O₂

[1164] Calcd.: C, 66.22; H, 5.23; N, 18.17.

[1165] Found: C, 66.24; H, 4.98; N, 18.37.

Reference Example 2-75

[1166] 2-[[3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]nicotinic acid

[1167] Following the procedure described in Reference Example 2-5, thetitle compound was prepared from 2-chloronicotinic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (72% yield).

[1168] mp: 252-254° C. (recrystallized from ethanol).

[1169] NMR (DMSO-d₆) δ: 2.26 (3H, s), 7.00 (1H, dd, J=4.6 Hz, 7.6 Hz),7.07 (1H, s), 7.32 (1H, ddd, J=1.4 Hz, 5.0 Hz, 7.0 Hz), 7.89 (1H, d,J=8.4 Hz), 7.95-8.04 (1H, m), 8.32 (1H, dd, J=2.0 Hz, 7.6 Hz), 8.48-8.54(2H, m), 13.28 (1H, br s), hidden (1H).

[1170] Elementary Analysis: for C₁₅H₁₃N₅O₂

[1171] Calcd.: C, 57.24; H, 3.52; N, 17.80.

[1172] Found: C, 57.13; H, 3.46; N, 17.72.

EXAMPLE 2-1

[1173] 4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1174] A solution of2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50.2 g,0.17 mol) in phosphorous oxychloride (120 mL, 1.27 mol) was heated underreflux for 1 hour. The solution was cooled to room temperature andconcentrated under reduced pressure, and the residue was poured intoiced water. The solution was made basic by the addition of a sodiumhydroxide solution, and the organic matter was extracted withchloroform. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (chloroform:methanol=98:2) to give the titlecompound (21.5 g, 43% yield).

[1175] mp: 157-159° C. (recrystallized from ethyl acetate/hexane).

[1176] NMR (CDCl₃) δ: 3.00 (3H, s), 7.21-7.25 (1H, m), 7.60-7.64 (1H,m), 7.78-7.87 (1H, m), 7.90-7.99 (1H, m), 8.18 (1H, dd, J=0.8 Hz, 8.4Hz), 8.41 (1H, dt, J=0.8 Hz, 7.6 Hz), 8.68 (1H, d, J=4.8 Hz), 8.85 (1H,d, J=8.4 Hz).

[1177] Elementary Analysis: for C₁₆H₁₁ClN₄

[1178] Calcd.: C, 65.20; H, 3.76; N, 19.01; Cl, 12.03.

[1179] Found: C, 65.22; H, 3.73; N, 19.13; Cl, 11.76.

EXAMPLE 2-2

[1180] 3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1181] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.44 g,4.89 mmol) and sodium azide (0.35 g, 5.37 mmol) in N,N-dimethylformamide(10 mL) was heated under reflux at 100° C. for 30 minutes. The solutionwas cooled to room temperature, poured into water, and the organicmatter was extracted with chloroform. The extract was washed withsaturated brine and water and dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. To a solution of theresidue thus obtained in ethanol (70 mL), 10% palladium-carbon (2 g, 50%hydrate) was added and the mixture was stirred at room temperature underhydrogen atmosphere for 1 hour. The solution was filtered to remove thecatalyst, and the filtrate was concentrated under reduced pressure. Theresidue thus obtained was purified by basic silica gel columnchromatography (ethyl acetate:methanol=95:5) to give the title compound(760 mg, 57% yield).

[1182] mp: 210-213° C. (recrystallized from methanol/ethylacetate/hexane).

[1183] NMR (CDCl₃) δ: 2.80 (3H, s), 5.60 (2H, br s), 7.13-7.22 (1H, m),7.29-7.40 (1H, m), 7.63-7.75 (1H, m), 7.80-7.95 (2H, m), 7.98-8.05 (1H,m), 8.60-8.67 (1H, m), 8.90-8.98 (1H, m).

[1184] Elementary Analysis: for C₁₆H₁₃N₅

[1185] Calcd.: C, 69.80; H, 4.76; N. 25.44.

[1186] Found: C, 69.61; H, 4.70; N, 25.30.

EXAMPLE 2-3

[1187] 3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[1188] To a solution of3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine (1.56 g,5.65 mmol) in ethanol (5 mL), a solution of 4N hydrochloric acid/ethylacetate (10 mL) was added, and the solution was concentrated underreduced pressure. The residue thus obtained was recrystallized fromethanol to give the title compound (1.41 g, 80% yield).

[1189] mp: 268-271° C. (recrystallized from ethanol).

[1190] NMR (DMSO-d₆) δ: 2.85 (3H, s), 7.46-7.52 (1H, m), 7.59-7.67 (1H,m), 7.92-8.04 (2H, m), 8.09-8.18 (1H, m), 8.44 (1H, d, J=8.4 Hz),8.68-8.70 (1H, m), 8.82-8.87 (2H, m), 9.85 (2H, br s).

[1191] Elementary Analysis: for C₁₆H₁₃N₅.HCl.1.6H₂O

[1192] Calcd.: C, 56.42; H, 5.09; N, 20.56; Cl, 10.41.

[1193] Found: C, 56.20; H, 5.01; N, 20.60; Cl, 10.39.

EXAMPLE 2-4

[1194]N-Methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]aminehydrochloride

[1195] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.8 g,2.71 mmol) in 40% methylamine in methanol (21 mL, 0.27 mol) was heatedunder reflux at 100° C. for 4 hours in a sealed stainless tube. Thesolution was allowed to cool to room temperature, and concentrated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (chloroform:methanol=98:2) to give an oil ofN-methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine.To a solution of the oil in ethanol (10 mL), was added a saturatedhydrochloric acid/ethanol solution (10 mL), and the solvent wasevaporated under reduced pressure. The residue thus obtained wasrecrystallized from methanol/ethyl acetate to give the title compound(0.63 g, 64% yield).

[1196] mp: 229-232° C. (recrystallized from ethyl acetate/methanol).

[1197] NMR (DMSO-d₆) δ: 2.84 (3H, s), 3.57 (3H, s), 7.45-7.62 (2H, m),7.87-8.00 (2H, m), 8.14 (1H, d, J=1.8 Hz, 7.3 Hz), 8.34 (1H, d, J=8.1Hz), 8.55-8.71 (1H, m), 8.72-8.82 (1H, m), 10.40 (1H, br s).

[1198] Elementary Analysis: for C₁₇H₁₅N₅.1.5HClH₂O

[1199] Calcd.: C, 56.40; H, 5.15; N, 19.34.

[1200] Found: C, 56.29; H, 5.10; N, 19.08.

EXAMPLE 2-5

[1201]N-Cyclopropyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]aminehydrochloride

[1202] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.7 g,2.37 mmol) and cyclopropylamine (0.7 g, 73.6 mmol) in tetrahydrofuran(20 mL) was heated under reflux at 100° C. overnight in a sealedstainless tube. The solution was cooled to room temperature, andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (chloroform:methanol=93:7)to giveN-cyclopropyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine.To a solution of the compound above in ethanol (10 mL), a saturatedhydrochloric acid/ethanol solution (10 mL) was added and the solvent wasevaporated under reduced pressure. The residue thus obtained wasrecrystallized from methanol/ethyl acetate to give the title compound(0.52 g, 56% yield).

[1203] mp: 208-211° C. (recrystallized from ethyl acetate/methanol). NMR(DMSO-d₆) δ: 0.95-1.20 (4H, m), 2.88 (3H, s), 3.55 (1H, m), 7.45-7.65(2H, m), 7.92-8.03 (2H, m), 8.15 (1H, t, J=7.7 Hz), 8.40 (1H, d, J=9.2Hz), 8.67-8.75 (1H, m), 8.80-8.91 (1H, m), 9.80 (1H, br s).

[1204] Elementary Analysis: for C₁₉H₁₇N₅.HCl.2H₂O

[1205] Calcd.: C, 58.84; H, 5.72; N, 18.06.

[1206] Found: C, 59.14; H, 5.44; N, 17.83.

EXAMPLE 2-6

[1207]N-[3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]-N-propylamine

[1208] A mixture of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.47 g,5.00 mmol) and propylamine (2.96 g, 50.0 mmol) was heated and stirred at100° C. for 6 hours in a sealed stainless tube. The solution was allowedto cool to room temperature and poured into water, and the organicmatter was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and evaporatedunder reduced pressure. The residue thus obtained was purified by basicsilica gel column chromatography (hexane:ethyl acetate=1:1), and theresulting crystals were recrystallized from ethyl acetate/hexane to givethe title compound (1.14 g, 72% yield).

[1209] mp: 121-122° C. (recrystallized from ethyl acetate/hexane). NMR(CDCl₃) δ: 1.08 (3H, t, J=7.4 Hz), 1.73-1.92 (2H, m), 2.91 (3H, s), 3.81(2H, dt, J=5.4 Hz, 7.0 Hz), 5.17 (1H, br t), 7.17 (1H, ddd, J=0.8 Hz,4.8 Hz, 7.4 Hz), 7.26-7.34 (1H, m), 7.65 (1H, ddd, J=1.4 Hz, 6.6 Hz, 8.8Hz), 7.89 (1H, ddd, J=2.2 Hz, 7.4 Hz, 8.4 Hz), 8.00 (1H, dd, J=1.4 Hz,8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.63 (1H, ddd, J=0.8 Hz, 2.2 Hz, 4.8Hz), 8.97 (1H, d, J=8.4 Hz).

[1210] Elementary Analysis: for C₁₉H₁₉N₅

[1211] Calcd.: C, 71.90; H, 6.03; N, 22.07.

[1212] Found: C, 71.79; H, 6.17; N, 22.12.

EXAMPLE 2-7

[1213]N-Butyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine

[1214] Following the procedure described in Example 2-6, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andbutylamine (68% yield).

[1215] mp: 97-99° C. (recrystallized from ethyl acetate/hexane).

[1216] NMR (CDCl₃) δ: 0.99 (3H, t, J=7.0 Hz), 1.41-1.59 (2H, m),1.71-1.85 (2H, m), 2.90 (3H, s), 3.84 (2H, dt, J=5.2 Hz, 7.0 Hz), 5.15(1H, br t), 7.17 (1H, ddd, J=1.2 Hz, 4.8 Hz, 7.4 Hz), 7.26-7.34 (1H, m),7.65 (1H, ddd, J=1.4 Hz, 6.8 Hz, 8.6 Hz), 7.89 (1H, ddd, J=2.2 Hz, 7.4Hz, 8.4 Hz), 8.01 (1H, dd, J=1.4 Hz, 8.6 Hz), 8.14 (1H, dd, J=1.4 Hz,8.8 Hz), 8.63 (1H, ddd, J=0.8 Hz, 2.2 Hz, 4.8 Hz), 8.97 (1H, dd, J=1.2Hz, 8.4 Hz).

[1217] Elementary Analysis: for C₂₀H₂₁N₅

[1218] Calcd.: C, 72.48; H, 6.39; N, 21.13.

[1219] Found: C, 72.28; H, 6.37; N, 21.09.

EXAMPLE 2-8

[1220]N,N-Dimethyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine

[1221] 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(1.00 g, 3.39 mmol) was added to a 2M dimethylamine in tetrahydrofuransolution (5.00 mL, 10.0 mmol), and the solution was heated under refluxovernight at 100° C. in a sealed tube. The solution was cooled to roomtemperature and poured into water, and the organic matter was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and evaporated under reduced pressure.The residue thus obtained was purified by silica gel columnchromatography (ethyl acetate to ethyl acetate:methanol=9:1) to give thetitle compound (1.00 g, 97% yield). mp: 98-101° C. (recrystallized fromethyl acetate/hexane). NMR (CDCl₃) δ: 2.89 (3H, s), 3.39 (6H, s),7.16-7.22 (1H, m), 7.37-7.45 (1H, m), 7.66-7.74 (1H, m), 7.87-7.96 (1H,m), 8.12 (1H, d, J=9.0 Hz), 8.22 (1H, d, J=7.3 Hz), 8.64-8.67 (1H, m),8.94 (1H, d, J=8.4 Hz).

[1222] Elementary Analysis: for C₁₈H₁₇N₅

[1223] Calcd.: C, 71.27; H, 5.65, N, 23.09.

[1224] Found: C, 71.25; H, 5.64; N, 23.02.

EXAMPLE 2-9

[1225]N-Methyl-N-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]-N-propylamine

[1226] Following the procedure described in Example 2-6, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andN-methyl-N-propylamine (64% yield).

[1227] mp: 110-112° C. (recrystallized from ethyl acetate/hexane).

[1228] NMR (CDCl₃) δ: 0.89 (3H, t, J=7.4 Hz), 1.60-1.82 (2H, m), 2.89(3H, s), 3.34 (3H, s), 3.57 (2H, t, J=7.4 Hz), 7.19 (1H, ddd, J=1.0 Hz,4.8 Hz, 7.4 Hz), 7.41 (1H, ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz), 7.70 (1H,ddd, J=1.4 Hz, 6.6 Hz, 8.6 Hz), 7.91 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4Hz), 8.10-8.21 (2H, m), 8.65 (1H, ddd, J=1.0 Hz, 1.8 Hz, 4.8 Hz), 8.94(1H, td, J=1.0 Hz, 8.4 Hz).

[1229] Elementary Analysis: for C₂₀H₂₁N₅

[1230] Calcd.: C, 72.48; H, 6.39; N, 21.13.

[1231] Found: C, 72.47; H, 6.50; N, 21.15.

EXAMPLE 2-10

[1232]N-Butyl-N-methyl-[3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine

[1233] Following the procedure described in Example 2-6, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andN-butyl-N-methylamine (55% yield).

[1234] mp: 85-87° C. (recrystallized from ethyl acetate/hexane).

[1235] NMR (CDCl₃) δ: 0.87 (3H, t, J=7.4 Hz), 1.22-1.40 (2H, m),1.60-1.75 (2H, m), 2.89 (3H, s), 3.34 (3H, s), 3.60 (2H, t, J=7.6 Hz),7.19 (1H, ddd, J=1.2 Hz, 5.0 Hz, 7.4 Hz), 7.41 (1H, ddd, J=1.4 Hz, 6.6Hz, 8.8 Hz), 7.70 (1H, ddd, J=1.4 Hz, 6.6 Hz, 8.4 Hz), 7.91 (1H, ddd,J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.10-8.20 (2H, m), 8.65 (1H, ddd, J=0.6 Hz,1.8 Hz, 5.0 Hz), 8.94 (1H, ddd, J=0.6 Hz, 1.2 Hz, 8.4 Hz).

[1236] Elementary Analysis: for C₂₁H₂₃N₅

[1237] Calcd.: C, 73.02; H, 6.71; N, 20.27.

[1238] Found: C, 72.87; H, 6.68; N, 20.22.

EXAMPLE 2-11

[1239]3-Methyl-4-(4-morpholinyl)-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1240] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.47 g,5.00 mmol), morpholine (0.87 g, 10.0 mmol) and potassium carbonate (1.38g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was heated under refluxat 100° C. for 12 hours. The solution was cooled to room temperature,and concentrated under reduced pressure. The residue was poured intowater and organic matter was extracted with chloroform. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andevaporated under reduced pressure. The residue thus obtained waspurified by basic silica gel column chromatography(hexane:chloroform=3:1) to give the title compound (0.63 g, 36% yield).

[1241] mp: 203-205° C. (recrystallized from ethyl acetate).

[1242] NMR (CDCl₃) δ: 2.99 (3H, s), 3.61 (4H, t, J=4.5 Hz), 4.04 (4H, t,J=4.5 Hz), 7.21 (1H, ddd, J=0.8 Hz, 4.8 Hz, 7.4 Hz), 7.47 (1H, ddd,J=0.8 Hz, 6.6 Hz, 8.8 Hz), 7.83 (1H, ddd, J=0.8 Hz, 6.6 Hz, 8.8 Hz),7.92 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.17 (1H, dd, J=0.8 Hz, 8.8Hz), 8.38 (1H, ddd, J=0.6 Hz, 0.8 Hz, 8.8 Hz), 8.66 (1H, ddd, J=0.6 Hz,1.8 Hz, 4.8 Hz), 8.92 (1H, dd, J=0.8 Hz, 8.4 Hz).

[1243] Elementary Analysis: for C₂₀H₁₉N₅O

[1244] Calcd.: C, 69.55; H, 5.54; N, 20.28.

[1245] Found: C, 69.47; H, 5.43; N, 20.26.

EXAMPLE 2-12

[1246]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1247] A mixture of methanesulfonic acid (120 mL, 1.85 mmol) andphosphorus pentoxide (24.0 g, 0.17 mol) was heated to 100° C. To themixture stirred at the same temperature, powdery2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazole-5-yl]amino]benzoic acid (24.0g, 82 mmol) was added gradually in small portions. The mixture washeated and stirred at the same temperature for 15 minutes. After thesolution was allowed to cool to room temperature, iced water was addedto the solution. The solution was made basic by the addition of anaqueous sodium hydroxide solution, and the organic matter was extractedwith chloroform. The extract was washed with saturated brine and water,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue thus obtained waspurified by basic silica gel column chromatography (chloroform). Thecrystals thus obtained we dissolved in a hot mixture of ethyl acetate(300 mL) and methanol (300 mL), and the solution was heated under refluxfor 30 minutes in the presence of activated carbon (2.5 g). The hotsolution was filtered and the solvents were evaporated under reducedpressure. The residue was recrystallized from ethyl acetate to give thetitle compound (15.1 g, 67% yield).

[1248] mp: 199-200° C. (recrystallized from ethyl acetate).

[1249] NMR (CDCl₃) δ: 2.77 (3H, s), 7.19-7.26 (1H, m), 7.33 (1H, td,J=1.2 Hz, 8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.61-7.70 (1H, m), 7.90 (1H,td, J=l.6 Hz, 8.4 Hz), 8.02 (1H, d, J=8.4 Hz), 8.46-8.50 (2H, m), 11.45(1H, br s).

[1250] Elementary Analysis: for C₁₆H₁₂N₄O

[1251] Calcd.: C, 69.55; H, 4.38; N, 20.28.

[1252] Found: C, 69.47; H, 4.26; N, 20.33.

EXAMPLE 2-13

[1253]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1254] To a solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (34.9 g,0.12 mol) in ethanol (500 mL) was added 6N hydrochloric acid (50 mL,0.30 mol), and the mixture was heated under reflux for 2 hours. Thesolution was cooled to room temperature, and concentrated under reducedpressure. The residue was made basic by the addition of an aqueoussodium hydroxide solution, and the organic matter was extracted withchloroform. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=95:5) to give the title compound(25.8 g, 79% yield).

EXAMPLE 2-14

[1255]3,9-Dimethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1256] To an ice-cold solution of3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(1.11 g, 4.0 mmol) in N,N-dimethylformamide (16 mL), sodium hydride(oiliness, content 60%, 0.19 g, 4.8 mmol) was added and the mixture wasstirred at room temperature for 1 hour. Subsequently, iodomethane (2.5mL, 40.2 mmol) was added thereto at 0° C., and the mixture was stirredat room temperature for additional 16 hours. To the mixture was addediced water, and the mixture was made basic by the addition of an aqueoussodium hydroxide solution, and the organic matter was extracted withchloroform. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by basicsilica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1)to give the title compound (0.47 g, 40% yield).

[1257] mp: 192-193° C. (recrystallized from ethyl acetate/diethylether).

[1258] NMR (CDCl₃) δ: 2.75 (3H, s), 3.57 (3H, s), 7.30-7.48 (3H, m),7.55-7.66 (1H, m), 7.83-8.00 (2H, m), 8.50-8.56 (2H, m).

[1259] Elementary Analysis: for C₁₇H₁₄N₄O

[1260] Calcd.: C, 70.33; H, 4.86; N, 19.30.

[1261] Found: C, 70.34; H, 4.87; N, 19.41.

EXAMPLE 2-15

[1262] 4-Methoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1263] 4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(1.00 g, 3.39 mmol) and 28% sodium methoxide in methanol (9.69 g, 50.2mmol) were added to a mixture of methanol (30 mL) and tetrahydrofuran(30 mL), and the solution was heated under reflux for 2.5 hours. Afterthe solution was cooled to room temperature, the solvents wereevaporated under reduced pressure. The residue was poured into water,and the organic matter was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue thusobtained was purified by silica gel column chromatography (hexane:ethylacetate=l:1 to ethyl acetate) to give the title compound (0.73 g, 50%yield).

[1264] mp: 44-47° C. (recrystallized from ethyl acetate/hexane/petroleumether).

[1265] NMR (CDCl₃) (: 2.99 (3H, s), 4.28 (3H, s), 7.21 (1H, ddd, J=1.1Hz, 4.8 Hz, 7.4 Hz), 7.46-7.54 (1H, m), 7.74-7.82 (1H, m), 7.93 (1H,ddd, J=1.8 Hz, 7.4 Hz, 8.6 Hz), 8.17 (1H, d, J=8.0 Hz), 8.28 (1H, ddd,J=0.8 Hz, 1.4 Hz, 8.6 Hz), 8.67 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz),8.91 (1H, d, J=8.4 Hz).

EXAMPLE 2-16

[1266] 4-Ethoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1267] To an ice-cold solution of3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(2.76 g, 10 mmol) in N,N-dimethylformamide (30 mL) was added sodiumhydride (oiliness, content 60%, 0.48 g, 12 mmol), and the mixture wasstirred at room temperature for 1 hour. Subsequently, iodoethane (1.96mL, 24.5 mmol) was added to the mixtuer and the mixture was stirred atroom temperature further for 16 hours. Ice water was added to themixture, and the organic matter was extracted with ethyl acetate. Theextract was washed with saturated brine and water, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue thus obtained was purified by basic silicagel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) togive the title compound (1.02 g, 34% yield).

[1268] mp: 121-123° C. (recrystallized from ethyl acetate/hexane).

[1269] NMR (CDCl₃) δ: 1.64 (3H, t, J=7.0 Hz), 2.92 (3H, s), 4.47 (2H, q,J=7.0 Hz), 7.16-7.23 (1H, m), 7.43-7.53 (1H, m), 7.73-7.82 (1H, m),7.88-7.98 (1H, m), 8.13-8.30 (2H, m), 8.64-8.69 (1H, m), 8.93 (1H, d,J=8.4 Hz).

[1270] Elementary Analysis: for C₁₈H₁₆N₄O

[1271] Calcd.: C, 71.04; H. 5.30; N. 18.41.

[1272] Found: C, 70.84; H, 5.25; N, 18.28.

EXAMPLE 2-17

[1273] 3-Methyl-4-propoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1274] Following the procedure described in Example 2-16, the titlecompound was prepared from3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand 1-iodopropane (62% yield).

[1275] mp: 103-105° C. (recrystallized from ethyl acetate/hexane).

[1276] NMR (CDCl₃) δ: 1.20 (3H, t, J=7.3 Hz), 1.97-2.17 (2H, m), 2.92(3H, s), 4.34 (2H, t, J=6.6 Hz), 7.17-7.25 (1H, m), 7.43-7.53 (1H, m),7.72-7.82 (1H, m), 7.88-7.98 (1H, m), 8.13-8.19 (1H, m), 8.23-8.31 (1H,m), 8.64-8.69 (1H, m), 8.92 (1H, d, J=8.4 Hz).

EXAMPLE 2-18

[1277] 4-Isopropoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1278] Following the procedure described in Example 2-16, the titlecompound was prepared from3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand 2-iodopropane (37% yield).

[1279] mp: 93-96° C. (recrystallized from ethyl acetate/hexane).

[1280] NMR (CDCl₃) δ: 1.48 (6H, d, J=6.4 Hz), 2.92 (3H, s), 4.89 (1H,m), 7.17-7.25 (1H, m), 7.42-7.51 (1H, m), 7.72-7.80 (1H, m), 7.88-7.98(1H, m), 8.12-8.27 (2H, m), 8.64-8.69 (1H, m), 8.93 (1H, d, J=8.4 Hz).

[1281] Elementary Analysis: for C₁₉H₁₈N₄O.H₂O

[1282] Calcd.: C, 67.84; H, 5.99; N, 16.66.

[1283] Found: C, 67.55; H, 6.26; N, 16.66.

EXAMPLE 2-19

[1284] 4-Butoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1285] To an ice-cold solution of 1-butanol (5.0 g, 68 mmol) intetrahydrofuran (15 mL), sodium hydride (oiliness, content 60%, 0.41 g,17 mmol) was added at room temperature and the mixture was stirred for15 minutes. Subsequently,4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g,3.39 mmol) was added to the mixture at 0° C., and the mixture was heatedunder reflux for another 1 hour. After the reaction solution was cooledto room temperature, the reaction solvent was concentrated andevaporated under reduced pressure. To the reaction mixture was addediced water and the mixture was neutralized by the addition of dilutehydrochloric acid, and the organic matter was extracted with ethylacetate. The extract was washed with saturated brine and water and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (ethyl acetate) to give the title compound (0.29g, 26% yield). mp: 59-61° C. (recrystallized from petroleumether/hexane). NMR (CDCl₃) δ: 1.06 (3H, t, J=7.3 Hz), 1.56-1.75 (2H, m),1.95-2.10 (2H, m), 2.91 (3H, s), 4.37 (2H, t, J=6.6 Hz), 7.16-7.26 (1H,m), 7.43-7.54 (1H, m), 7.72-7.84 (1H, m), 7.88-7.98 (1H, m), 8.15 (1H,d, J=8.4 Hz), 8.31 (1H, d, J=8.4 Hz), 8.64-8.70 (1H, m), 8.92 (1H, d,J=8.4 Hz).

EXAMPLE 2-20

[1286] 4-Isobutoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1287] To an ice-cold solution of3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(1.93 g, 7.0 mmol) in N,N-dimethylformamide (30 mL), sodium hydride(oiliness, content 60%, 0.42 g, 10.5 mmol) was added and the mixture wasstirred at room temperature for 1 hour. Subsequently, isobutyl iodide(2.0 mL, 17.4 mmol) was added to the mixture, and the mixture wasstirred at room temperature for 16 hours, and heated under reflux at 70°C. for 8 hours. The reaction solution was allowed to cool and iced waterwas added to the mixture, and the organic matter was extracted withethyl acetate. The extract was washed with saturated brine and water anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by basicsilica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1)to give the title compound (0.54 g, 23% yield).

[1288] mp: 117-120° C. (recrystallized from ethyl acetate/hexane).

[1289] NMR (CDCl₃) δ: 1.22 (6H, d, J=6.8 Hz), 2.30 (1H, m), 2.91 (3H,s), 4.14 (2H, d, J=6.2 Hz), 7.17-7.27 (1H, m), 7.44-7.52 (1H, m),7.72-7.81 (1H, m), 7.88-7.98 (1H, m), 8.16 (1H, d, J=8.4 Hz), 8.23-8.29(1H, m), 8.64-8.68 (1H, m), 8.93 (1H, d, J=8.4 Hz).

[1290] Elementary Analysis: for C₂₀H₂₀N₄O

[1291] Calcd.: C, 72.27; H, 6.06; N, 16.86.

[1292] Found: C, 72.24; H, 6.21; N, 17.11.

EXAMPLE 2-21

[1293]4-Cyclopentyloxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1294] Following the procedure described in Example 2-20, the titlecompound was prepared from3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand bromocyclopentane (19% yield).

[1295] mp: 102-105° C. (recrystallized from ethyl acetate/hexane).

[1296] NMR (CDCl₃) δ: 1.60-2.20 (8H, m), 2.92 (3H, s), 5.10-5.22 (1H,m), 7.17-7.25 (1H, m), 7.41-7.50 (1H, m), 7.70-7.80 (1H, m), 7.88-7.98(1H, m), 8.14 (1H, d, J=8.8 Hz), 8.25 (1H, dd, J=1.1 Hz, 8.8 Hz),8.63-8.69 (1H, m), 8.93 (1H, d, J=8.4 Hz).

EXAMPLE 2-22

[1297]4-Cyclohexyloxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1298] Following the procedure described in Example 2-20, the titlecompound was prepared from3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand bromocyclohexane (11% yield).

[1299] mp: 88-91° C. (recrystallized from ethyl acetate/hexane).

[1300] NMR (CDCl₃) δ: 1.20-2.20 (10H, m), 2.92 (3H, s), 4.40-4.60 (1H,m), 7.15-7.28 (1H, m), 7.46 (1H, t, J=7.6 Hz), 7.65-7.81 (1H, m),7.87-7.98 (1H, m), 8.14 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=8.8 Hz),8.63-8.70 (1H, m), 8.91 (1H, d, J=8.6 Hz).

[1301] Elementary Analysis: for C₂₂H₂₂N₄O.1.5H₂O

[1302] Calcd.: C, 68.55; H, 6.54; N, 14.53.

[1303] Found: C, 68.57; H, 6.62; N, 14.40.

EXAMPLE 2-23

[1304]4-Benzyloxy-3-methyl-6-nitro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1305] Following the procedure described in Example 2-19, the titlecompound was prepared from4-chloro-3-methyl-6-nitro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand benzyl alcohol (6% yield).

[1306] mp: 178-180° C. (recrystallized from ethyl acetate/methanol).

[1307] NMR (CDCl₃) δ: 2.82 (3H, s), 5.51 (2H, s), 7.28 (1H, ddd, J=1.0Hz, 4.8 Hz, 7.4 Hz), 7.42 (5H, s), 7.96 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4Hz), 8.21 (1H, dd, J=0.8 Hz, 9.6 Hz), 8.47 (1H, dd, J=2.6 Hz, 9.6 Hz),8.70 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.76 (1H, ddd, J=0.8 Hz, 1.0Hz, 8.4 Hz), 9.10 (1H, dd, J=0.8 Hz, 2.6 Hz).

[1308] Elementary Analysis: for C₂₃H₁₇N₅O₃

[1309] Calcd.: C, 67.15; H, 4.16; N, 17.02.

[1310] Found: C, 67.02; H, 4.05; N, 17.08.

EXAMPLE 2-24

[1311]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-thione

[1312] A solution of3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(13.94 g, 50.5 mmol) and Lawesson's Reagent (12.5 g, 30.9 mmol) intoluene (750 mL) was heated under reflux for 1 hour. The reactionsolution was cooled to room temperature, and the resulting crudecrystals were collected by filtration. The crystals were recrystallizedfrom ethyl acetate to give the title compound (13.11 g, 89% yield).

[1313] mp: 252-253° C. (recrystallized from ethyl acetate).

[1314] NMR (CDCl₃) δ: 2.96 (3H, s), 7.23-7.28 (1H, m), 7.37-7.50 (2H,m), 7.65-7.73 (1H, m), 7.88-7.97 (1H, m), 8.05 (1H, d, J=7.6 Hz), 8.51(1H, d, J=4.2 Hz), 9.08 (1H, d, J=8.6 Hz), 12.01 (1H, br s).

[1315] Elementary Analysis: for C₁₆H₁₂N₄S

[1316] Calcd.: C, 65.73; H, 4.14; N, 19.16.

[1317] Found: C, 65.53; H, 4.10; N, 19.04.

EXAMPLE 2-25

[1318]4-(Isopropylsulfanyl)-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1319] Following the procedure described in Example 2-27 describedbelow, the title compound was prepared from3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-thioneand 2-iodopropane (72% yield).

[1320] mp: 113-114° C. (recrystallized from isopropylether/hexane).

[1321] NMR (CDCl₃) δ: 1.29 (6H, d, J=7.0 Hz), 3.08 (3H, s), 3.42-3.55(1H, m), 7.19-7.27 (1H, m), 7.55-7.63 (1H, m), 7.76-7.85 (1H, m),7.90-7.99 (1H, m), 8.20 (1H, dd, J=0.8 Hz, 8.4 Hz), 8.66-8.70 (1H, m),8.75 (1H, dd, J=0.8 Hz, 8.5 Hz), 8.89 (1H, d, J=8.4 Hz).

[1322] Elementary Analysis: for C₁₉H₁₈N₄S

[1323] Calcd.: C, 68.24; H, 5.42; N, 16.75.

[1324] Found: C, 68.36; H, 5.59; N. 16.54.

EXAMPLE 2-26

[1325]4-(Isopropylsulfinyl)-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1326] Following the procedure described in Example 2-28 describedbelow, the title compound was prepared from4-(isopropylsulfanyl)-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand m-chloroperbenzoic acid (82% yield).

[1327] mp: 125-126° C. (recrystallized from ethyl acetate).

[1328] NMR (CDCl₃) δ: 1.06 (3H, d, J=7.0 Hz), 1.62 (3H, d, J=7.0 Hz),2.97 (3H, s), 3.71-3.85 (1H, m), 7.25-7.31 (1H, m), 7.56-7.65 (1H, m),7.83-7.91 (1H, m), 7.93-8.02 (1H, m), 8.27 (1H, dd, J=0.6 Hz, 8.2 Hz),8.68-8.71 (1H, m), 8.82 (1H, d, J=8.4 Hz), 9.27-9.34 (1H, m).

EXAMPLE 2-27

[1329]3-Methyl-4-(propylsulfanyl)-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1330] A solution of3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-thione(4.04 g, 13.8 mmol), 1-iodopropane (6.80 mL, 69.7 mmol) and potassiumcarbonate (3.79 g, 27.5 mmol) in N,N-dimethylformamide (25 mL) wasstirred at room temperature for 8 hours. The reaction solvent wasevaporated under reduced pressure. Water was added to the residue, andthe organic matter was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue thusobtained was recrystallized from ethyl acetate/hexane to give the titlecompound (3.83 g, 83% yield).

[1331] mp: 91-93° C. (recrystallized from ethyl acetate/hexane).

[1332] NMR (CDCl₃) δ: 0.93 (3H, t, J=7.4 Hz), 1.53-1.64 (2H, m), 2.99(2H, t, J=7.2 Hz), 3.09 (3H, s), 7.19-7.25 (1H, m), 7.55-7.64 (1H, m),7.76-7.85 (1H, m), 7.89-7.98 (1H, m), 8.20 (1H, d, J=8.4 Hz), 8.66-8.69(1H, m), 8.73 (1H, dd, J=0.8 Hz, 8.8 Hz), 8.89 (1H, d, J=8.2 Hz).

[1333] Elementary Analysis: for C₁₉H₁₈N₄S.H₂O

[1334] Calcd.: C, 64.75; H, 5.72; N, 15.90.

[1335] Found: C, 64.48; H, 5.79; N, 15.90.

EXAMPLE 2-28

[1336]3-Methyl-4-(propylsulfinyl)-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1337] A solution of m-chloroperbenzoic acid (0.96 g, 5.6 mmol) inchloroform (55 mL) was added dropwise to a solution of3-methyl-4-propylsulfanyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(1.54 g, 4.6 mmol) in chloroform (55 mL) at a temperature of lower than0° C., and the mixture was stirred at the same temperature for another2.5 hours. The reaction solution was washed with an aqueous saturatedsodium bicarbonate solution and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography (hexane:chloroform:ethyl acetate=2:1:1 to 1:1:1) to givethe title compound (0.84 g, 52% yield).

[1338] mp: 125-127° C. (recrystallized from ethyl acetate).

[1339] NMR (CDCl₃) δ: 1.30 (3H, t, J=7.2 Hz), 1.75-2.05 (2H, m), 2.96(3H, s), 3.02-3.16 (1H, m), 3.58-3.71 (1H, m), 7.24-7.31 (1H, m),7.57-7.66 (1H, m), 7.83-7.91 (1H, m), 7.93-8.01 (1H, m), 8.27 (1H, d,J=8.4 Hz), 8.68-8.71 (1H, m), 8.82 (1H, dd, J=0.8 Hz, 7.8 Hz), 9.36 (1H,d, J=8.4 Hz).

EXAMPLE 2-29

[1340] 4-Chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1341] To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol)in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise atroom temperature, and the mixture was stirred overnight at roomtemperature. The reaction solvent and excess diketene were concentratedand evaporated under reduced pressure, and tetrachloride (80 mL) wereadded to the residue, and subsequently acetic anhydride (27 g, 0.265mol) was added thereto, and the mixture was heated under reflux for 3hours. The reaction solvent and excess acetic anhydride wereconcentrated and evaporated under reduced pressure, and the resultingpowder was collected, and washed with diethylether to give crude5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). Asolution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine(7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1hour. The reaction solution was allowed to cool to room temperature, thereaction solvent was concentrated and evaporated under reduced pressure.A solution of the residue in phosphorous oxychloride (45.8 g, 0.3 mol)was heated and stirred at 100° C. for 1 hour. The reaction solution wasallowed to cool to room temperature, and the solvent was concentratedand evaporated under reduced pressure, and the residue was poured intoiced water. A sodium hydroxide solution was added to the mixture tobecome basic, and the organic matter was extracted with chloroform. Theextract was washed with saturated brine and water, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (ethyl acetate:methanol=98:2) to give the titlecompound (4.4 g, 24% yield)

[1342] mp: 167-169° C. (recrystallized from ethyl acetate/methanol).

[1343] NMR (CDCl₃) δ: 2.98 (3H, s), 3.08 (3H, s), 7.18-7.33 (2H, m),7.60 (1H, q, J=7.1 Hz), 7.87-7.97 (1H, m), 8.01 (1H, d, J=8.1 Hz),8.64-8.70 (1H, m), 8.83 (1H, d, J=8.4 Hz).

[1344] Elementary Analysis: for C₁₇H₁₃ClN₄

[1345] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[1346] Found: C, 66.18; H, 4.22; N, 18.17; Cl, 11.54.

EXAMPLE 2-30

[1347] 3,5-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1348] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (58% yield).

[1349] mp: 252-255° C. (recrystallized from methanol).

[1350] NMR (DMSO-d₆) δ: 2.82 (3H, s), 2.99 (3H, s), 6.73 (2H, br s),7.04 (1H, d, J=6.2 Hz), 7.22-7.31 (1H, m), 7.47 (1H, t, J=7.3 Hz), 7.63(1H, d, J=8.8 Hz), 7.93-8.07 (1H, m), 8.50-8.56 (1H, m), 8.71 (1H, d,J=8.4 Hz).

[1351] Elementary Analysis: for C₁₇H₁₅N.

[1352] Calcd.: C, 70.57; H, 5.23; N, 24.21.

[1353] Found: C, 70.79; H, 5.17; N, 23.81.

EXAMPLE 2-31

[1354]3,5-Dimethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1355] A solution of4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.65g, 5.34 mmol), sodium iodide (0.96 g, 6.41 mmol) and conc. hydrochloricacid (1 mL) in dimethylsulfoxide (20 mL) was heated and stirred at 100°C. for 2 hours. The solution was allowed to cool to room temperature,and the residue was poured into water. The solution was made basic bythe addition of an aqueous sodium hydroxide solution, and the organicmatter was extracted with 10% methanol/chloroform. The extract waswashed with saturated brine and water and dried over anhydrous magnesiumsulfate, and the solvents were evaporated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(ethyl acetate:hexane=90:10) to give the title compound (1.13 g, 73%yield).

[1356] mp: 183-186° C. (recrystallized from ethyl acetate).

[1357] NMR (CDCl₃) δ: 2.73 (3H, s), 2.99 (3H, s), 7.01 (1H, d, J=7.3Hz), 7.15-7.28 (2H, m), 7.44 (1H, t, J=7.9 Hz), 7.82-8.02 (2H, m),8.43-8.49 (1H, m), 11.18 (1H, br s).

[1358] Elementary Analysis: for C₁₇H₁₄N₄O

[1359] Calcd.: C, 70.33; H, 4.86; N, 19.36.

[1360] Found: C, 70.46; H, 4.87; N, 19.27.

EXAMPLE 2-32

[1361] 4-Chloro-3,6-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1362] Following the procedure described in Example 2-1, the titlecompound was prepared from5-methyl-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(56% yield).

[1363] mp: 158-160° C. (recrystallized from ethyl acetate).

[1364] NMR (CDCl₃) δ: 2.61 (3H, s), 2.99 (3H, s), 7.19-7.28 (1H, m),7.65 (1H, dd, J=1.8 Hz, 8.8 Hz), 7.88-7.98 (1H, m), 8.07 (1H, d, J=8.8Hz), 8.13 (1H, br s), 8.64-8.70 (1H, m), 8.82 (1H, d, J=8.4 Hz).

[1365] Elementary Analysis: for C₁₇H₁₃ClN₄.1.5H₂O

[1366] Calcd.: C, 60.81; H, 4.80; N, 16.69.

[1367] Found: C, 60.90; H, 4.88; N, 16.81.

EXAMPLE 2-33

[1368] 3,6-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[1369] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-3,6-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (62% yield).

[1370] mp: 287-290° C. (recrystallized from ethanol).

[1371] NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.82 (3H, s), 7.42-7.50 (1H, m),7.73-7.81 (1H, m), 7.89 (1H, d, J=8.1 Hz), 8.05-8.15 (1H, m), 8.29 (1H,d, J=8.4 Hz), 8.60-8.68 (2H, m), 9.80 (2H, br s).

[1372] Elementary Analysis: for C₁₇H₁₅N₅.HClH₂O

[1373] Calcd.: C, 59.39; H, 5.28; N, 20.37.

[1374] Found: C, 59.01; H, 5.29; N, 20.25.

EXAMPLE 2-34

[1375]3,6-Dimethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1376] Following the procedure described in Example 2-12, the titlecompound was prepared from5-methyl-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(57% yield).

[1377] mp: 198-200° C. (recrystallized from ethanol).

[1378] NMR (CDCl₃) δ: 2.47 (3H, s), 2.76 (3H, s), 7.17-7.25 (1H, m),7.34 (1H, d, J=8.4 Hz), 7.46 (1H, dd, J=1.8 Hz, 8.4 Hz), 7.78-8.12 (2H,m), 8.25 (1H, s), 8.45-8.50 (1H, m), 11.38 (1H, br s).

EXAMPLE 2-35

[1379] 4-Chloro-3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1380] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methyl-2-(2-oxypropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine(54% yield).

[1381] mp: 170-172° C. (recrystallized from ethyl acetate).

[1382] NMR (CDCl₃) δ: 2.87 (3H, s), 3.00 (3H, s), 7.20-7.28 (1H, m),7.48 (1H, dd, J=6.9 Hz, 8.4 Hz), 7.68 (1H, d, J=6.9 Hz), 7.90-8.00 (1H,m), 8.21-8.30 (1H, m), 8.65-8.73 (1H, m), 9.04 (1H, d, J=8.4 Hz).

[1383] Elementary Analysis: for C₁₇H₁₃ClN₄

[1384] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[1385] Found: C, 66.00; H, 4.08; N, 18.02; Cl, 11.43.

EXAMPLE 2-36

[1386] 3,8-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1387] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (67% yield).

[1388] mp: 208-211° C. (recrystallized from ethanol).

[1389] NMR (DMSO-d₆) δ: 2.69 (3H, s), 2.82 (3H, s), 7.15-7.32 (2H, m),7.39 (2H, br s), 7.56 (1H, d, J=6.6 Hz), 7.95-8.05 (1H, m), 8.29 (1H, d,J=8.1 Hz), 8.50-8.55 (1H, m), 8.90-9.10 (1H, m).

EXAMPLE 2-37

[1390] 3,8-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[1391] Following the procedure described in Example 2-3, the titlecompound was prepared from3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine (57%yield).

[1392] mp: 283-286° C. (recrystallized from ethanol).

[1393] NMR (DMSO-d₆) δ: 2.59 (3H, s), 2.77 (3H, s), 3.36 (2H, br s),7.30-7.55 (2H, m), 7.62-7.82 (1H, m), 8.00-8.20 (2H, m), 8.50-8.70 (2H,m).

[1394] Elementary Analysis: for C₁₇H₁₅N₅.HCl.0.5H₂O

[1395] Calcd.: C, 60.99; H, 5.12; N, 20.92; Cl, 10.59.

[1396] Found: C, 61.38; H, 4.96; N, 20.71; Cl, 10.64.

EXAMPLE 2-38

[1397]3,8-Dimethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1398] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (72%yield).

[1399] mp: 241-243° C. (recrystallized from ethanol).

[1400] NMR (CDCl₃) δ: 2.57 (3H, s), 2.75 (3H, s), 7.17-7.30 (2H, m),7.49 (1H, d, J=7.3 Hz), 7.84-7.92 (1H, m), 8.00 (1H, d, J=8.4 Hz), 8.32(1H, d, J=7.3 Hz), 8.46 (1H, d, J=4.0 Hz), 11.59 (1H, br s).

[1401] Elementary Analysis: for C₁₇H₁₄N₄O

[1402] Calcd.: C, 70.33; H, 4.86; N, 19.36.

[1403] Found: C, 70.25; H, 4.65; N, 19.21.

EXAMPLE 2-39

[1404]4-Chloro-3-methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]quinoline

[1405] A solution of2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-5-(trifluoromethyl)benzoicacid (14.0 g, 38.6 mmol) in phosphorous oxychloride (27.4 mL, 294 mmol)was heated under reflux for 1 hour. The solution was allowed to cool toroom temperature, and the reaction solvent was evaporated under reducedpressure, and the residue was poured into iced water. The solution wasneutralized by the addition of a sodium hydroxide solution, and theorganic matter was extracted with chloroform. The extract was washedwith saturated brine and water and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:chloroform=l:l to chloroform) to give the title compound (7.07g, 50% yield).

[1406] mp: 206° C. (recrystallized from ethyl acetate/methanol).

[1407] NMR (CDCl₃) δ: 3.01 (3H, s), 7.28 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4Hz), 7.91-7.99 (2H, m), 8.27 (1H, d, J=9.2 Hz), 8.68-8.77 (3H, m).

[1408] Elementary Analysis: for C₁₇H₁₀ClF₃N₄

[1409] Calcd.: C, 56.29; H, 2.78; N, 15.45; Cl, 9.77; F, 15.71.

[1410] Found: C, 56.23; H, 3.00; N, 15.23; Cl, 9.62; F, 15.70.

EXAMPLE 2-40

[1411]3-Methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-l,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1412] To a solution of4-chloro-3-methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]quinoline(6.50 g, 17.9 mmol) in ethanol (300 mL), 6N hydrochloric acid (10 mL, 60mmol) was added and the mixture was heated under reflux for 5 hours. Thesolution was allowed to cool to room temperature, and the resultingcrystals were collected by filtration. The crystals were washed withethanol and air dried, and recrystallized from ethanol to give the titlecompound (4.69 g, 76% yield).

[1413] mp: 250-251° C. (recrystallized from ethanol).

[1414] NMR (CDCl₃) δ: 2.74 (3H, s), 7.26 (1H, ddd, J=1.2 Hz, 5.0 Hz, 7.2Hz), 7.53 (1H, d, J=8.8 Hz), 7.84 (1H, dd, J=2.0 Hz, 8.8 Hz), 7.92 (1H,ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.03 (1H, ddd, J=1.0 Hz, 1.2 Hz, 8.4Hz), 8.49 (1H, ddd, J=1.0 Hz, 1.8 Hz, 5.0 Hz), 8.75 (1H, d, J=2.0 Hz),11.65 (1H, br s).

[1415] Elementary Analysis: for C₁₇H₁₁F₃N₄O

[1416] Calcd.: C, 59.31; H, 3.22; N, 16.27; F, 16.55.

[1417] Found: C, 59.23; H, 3.40; N, 16.00; F, 16.59.

EXAMPLE 2-41

[1418]4-Chloro-6-methoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1419] Following the procedure described in Example 2-1, the titlecompound was prepared from5-methoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (75% yield).

[1420] mp: 186-187° C. (recrystallized from ethyl acetate/methanol).

[1421] NMR (CDCl₃) δ: 2.98 (3H, s), 4.01 (3H, s), 7.22 (1H, ddd, J=1.0Hz, 4.8 Hz, 7.2 Hz), 7.48 (1H, dd, J=2.8 Hz, 9.2 Hz), 7.53 (1H, d, J=2.8Hz), 7.92 (1H, ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.06 (1H, dd, J=1.0 Hz,8.4 Hz), 8.67 (1H, dd, J=1.0 Hz, 4.8 Hz), 8.80 (1H, dd, J=1.0 Hz, 9.2Hz).

[1422] Elementary Analysis: for C₁₇H₁₃ClN₄O

[1423] Calcd.: C, 62.87; H, 4.03; N, 17.25; Cl, 10.92.

[1424] Found: C, 62.84; H, 4.14; N, 17.32; Cl, 10.88.

EXAMPLE 2-42

[1425]6-Methoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1426] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-6-methoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (61% yield).

[1427] mp: 267-268° C. (recrystallized from ethanol).

[1428] NMR (DMSO-d₆) δ: 2.82 (3H, s), 3.91 (3H, s), 7.25 (1H, ddd, J=0.8Hz, 4.8 Hz, 7.4 Hz), 7.28 (2H, br s), 7.35 (1H, dd, J=2.8 Hz, 9.4 Hz),7.73 (1H, d, J=9.4 Hz), 7.77 (1H, d, J=2.8 Hz), 7.98 (1H, ddd, J=2.0 Hz,7.4 Hz, 8.4 Hz), 8.52 (1H, ddd, J=0.8 Hz, 2.0 Hz, 4.8 Hz), 8.71 (1H, d,J=8.4 Hz).

[1429] Elementary Analysis: for C₁₇H₁₅N₅O

[1430] Calcd.: C, 66.87; H, 4.95; N, 22.94.

[1431] Found: C, 66.84; H, 4.91; N, 22.85.

EXAMPLE 2-43

[1432]6-Methoxy-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1433] Following the procedure described in Example 2-12, the titlecompound was prepared from5-methoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (55% yield).

[1434] mp: 227-229° C. (recrystallized from ethyl acetate).

[1435] NMR (CDCl₃) δ: 2.76 (3H, s), 3.92 (3H, s), 7.19 (1H, ddd, J=1.0Hz, 5.0 Hz, 7.4 Hz), 7.27 (1H, dd, J=3.0 Hz, 9.2 Hz), 7.38 (1H, d, J=9.2Hz), 7.83-7.92 (2H, m), 7.99 (1H, dd, J=1.0 Hz, 8.4 Hz), 8.46 (1H, ddd,J=1.0 Hz, 1.8 Hz, 5.0 Hz), 11.38 (1H, br s).

[1436] Elementary Analysis: for C₁₇H₁₄N₄O₂

[1437] Calcd.: C, 66.66; H, 4.61; N, 18.29.

[1438] Found: C, 66.68; H, 4.62; N, 18.31.

EXAMPLE 2-44

[1439] 4-Chloro-8-methoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1440] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methoxy-2-(2-oxypropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinopyridine (23% yield).

[1441] mp: 167-169° C. (recrystallized from ethyl acetate).

[1442] NMR (CDCl₃) δ: 3.00 (3H, s), 4.13 (3H, s), 7.15 (1H, d, J=7.7Hz), 7.20-7.28 (1H, m), 7.52 (1H, t, J=7.7 Hz), 7.91-8.03 (2H, m),8.65-8.71 (1H, m), 8.83 (1H, d, J=7.7 Hz).

[1443] Elementary Analysis: for C₁₇H₁₃ClN₄O

[1444] Calcd.: C, 62.87; H, 4.03; N, 17.25; Cl, 10.92.

[1445] Found: C, 62.88; H, 3.96; N, 17.16; Cl, 10.90.

EXAMPLE 2-45

[1446]8-Methoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[1447] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-8-methoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (65% yield).

[1448] mp: 248-251° C. (recrystallized from ethanol).

[1449] NMR (DMSO-d₆) δ: 2.73 (3H, s), 4.10 (3H, s), 7.53-7.60 (3H, m),7.85 (1H, d, J=8.4 Hz), 8.03-8.20 (2H, m), 8.53 (1H, br d, J=5.1 Hz),hidden (2H).

[1450] Elementary Analysis: for C₁₇H₁₅N₅O.HCl.1.5H₂O

[1451] Calcd.: C, 55.36; H, 5.19; N, 18.99; Cl, 9.61.

[1452] Found: C, 55.32; H, 4.95; N, 18.86; Cl, 9.54.

EXAMPLE 2-46

[1453]4-Chloro-6,7-dimethoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1454] Following the procedure described in Example 2-1, the titlecompound was prepared from4,5-dimethoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (32% yield).

[1455] mp: 248-251° C. (recrystallized from ethylacetate/methanol/chloroform).

[1456] NMR (CDCl₃) δ: 4.10 (6H, s), 2.96 (3H, s), 7.18-7.27 (1H, m),7.44 (1H, s), 7.51 (1H, s), 7.86-7,97 (1H, m), 8.65-8.76 (2H, m).

EXAMPLE 2-47

[1457]6,7-Dimethoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[1458] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-6,7-dimethoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (71% yield).

[1459] mp: 277-280° C. (recrystallized from methanol).

[1460] NMR (DMSO-d₆) δ: 2.71 (3H, s), 3.85 (3H, s), 3.91 (3H, s), 7.40(1H, br t, J=6.1 Hz), 7.56 (1H, s), 7.67 (1H, s), 7.74 (1H, br d, J=8.4Hz), 8.04 (1H, br t, J=8.4 Hz), 8.59 (1H, br d, J=6.1 Hz), hidden (2H).

[1461] Elementary Analysis: for C₁₈H₁₇N₅O₂.HCl.1.5H₂O

[1462] Calcd.: C, 54.20; H, 5.31; N, 17.56; Cl, 8.89.

[1463] Found: C, 53.95; H, 5.26; N, 17.49; Cl, 8.80.

EXAMPLE 2-48

[1464]6,7-Dimethoxy-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1465] Following the procedure described in Example 2-12, the titlecompound was prepared from4,5-dimethoxy-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (35% yield).

[1466] mp: 238-239° C. (recrystallized from ethyl acetate/methanol).

[1467] NMR (DMSO-d₆) δ: 2.60 (3H, s), 3.85 (3H, s), 3.93 (3H, s),7.35-7.42 (1H, m), 7.56 (1H, s), 7.66 (1H, s), 7.88 (1H, d, J=8.4 Hz),8.05 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.59-8.61 (1H, m), 11.78 (1H,br s).

[1468] Elementary Analysis: for C₁₈H₁₆N₄O₃.H₂O

[1469] Calcd.: C, 61.01; H, 5.12; N, 15.81.

[1470] Found: C, 60.81; H, 5.12; N, 15.86.

EXAMPLE 2-49

[1471]4-Chloro-3-methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1472] Following the procedure described in Example 2-1, the titlecompound was prepared from6-(methylsulfanyl)-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (29% yield).

[1473] mp: 182° C. (recrystallized from ethyl acetate/methanol).

[1474] NMR (CDCl₃) δ: 2.66 (3H, s), 2.98 (3H, s), 7.23 (1H, ddd, J=1.2Hz, 4.8 Hz, 7.4 Hz), 7.67 (1H, dd, J=2.2 Hz, 8.8 Hz), 7.92 (1H, ddd,J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.01-8.06 (2H, m), 8.67 (1H, ddd, J=0.6 Hz,1.8 Hz, 4.8 Hz), 8.78 (1H, ddd, J=0.6 Hz, 1.2 Hz, 8.4 Hz).

[1475] Elementary Analysis: for C₁₇H₁₃ClN₄S

[1476] Calcd.: C, 59.91; H, 3.84; N, 16.44; Cl, 10.40; S, 9.41.

[1477] Found: C, 59.86; H, 3.75; N, 16.59; Cl, 10.42; S, 9.39.

EXAMPLE 2-50

[1478]3-Methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1,9-dihydro-4H-parazolo[3,4-b]quinolin-4-one

[1479] Following the procedure described in Example 2-12, the titlecompound was prepared from6-(methylsulfanyl)-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (50% yield).

[1480] mp: 182-185° C. (recrystallized from methanol/ethyl acetate).

[1481] NMR (CDCl₃) δ: 2.58 (3H, s), 2.74 (3H, s), 7.17-7.25 (1H, m),7.35 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J=2.2 Hz, 8.8 Hz), 7.83-7.93 (1H,m), 7.99 (1H, d, J=8.8 Hz), 8.27 (1H, d, J=2.2 Hz), 8.43-8.49 (1H, m),11.42 (1H, br s).

[1482] Elementary Analysis: for C₁₇H₁₄N₄OS

[1483] Calcd.: C, 63.33; H, 4.38; N, 17.38.

[1484] Found: C, 62.92; H, 4.38; N, 17.09.

EXAMPLE 2-51

[1485]3-Methyl-6-(methylsulfinyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1486] A solution in a mixed solvent of methanol (40 mL),tetrahydrofuran (10 mL) and water (10 mL) of3-methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(1.00 g, 3.10 mmol) and sodium periodate (0.66 g, 3.10 mmol) was heatedunder reflux for 2 hours. The solution was allowed to cool to roomtemperature, and concentrated under reduced pressure. The residue waspoured into water, and the organic matter was extracted with chloroform.The extract was washed with saturated brine and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue thus obtained was purified by silica gel columnchromatography (chloroform to chloroform:methanol=98:2) to give thetitle compound (0.63 g, 61% yield).

[1487] mp: 268-269° C. (recrystallized from ethanol). NMR (DMSO-d₆) δ:2.63 (3H, s), 2.81 (3H, s), 7.39-7.45 (1H, m), 7.91 (1H, d, J=8.4 Hz),8.00 (1H, dd, J=2.2 Hz, 8.8 Hz), 8.03-8.12 (1H, m), 8.26 (1H d, J=8.8Hz), 8.50 (1H, d, J=2.2 Hz), 8.61-8.64 (1H, m), 12.16 (1H, br s).

[1488] Elementary Analysis: for C₁₇H₄₁N₄O₂S.0.2H₂O

[1489] Calcd.: C, 59.71; H, 4.24; N, 16.38; S, 9.38.

[1490] Found: C, 59.59; H, 3.95; N, 16.42; S, 9.48.

EXAMPLE 2-52

[1491]3-Methyl-6-(methylsulfonyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1492] A solution in a mixed solvent of methanol (40 mL),tetrahydrofuran (10 mL) and water (10 mL), of3-methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(1.00 g, 3.10 mmol), and sodium periodate (1.99 g, 9.30 mmol) was heatedunder reflux for 5 days. The solution was allowed to cool to roomtemperature, and concentrated under reduced pressure. The residue waspoured into water, and the organic matter was extracted with chloroform.The extract was washed with saturated brine and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue thus obtained was purified by silica gel columnchromatography (chloroform to chloroform:methanol=99:1) to give thetitle compound (0.17 g, 15% yield). mp: >300° C. (recrystallized fromchloroform/methanol). NMR (DMSO-d₆) δ: 2.63 (3H, s), 3.29 (3H, s), 7.43(1H, ddd, J=1.2 Hz, 4.8 Hz, 7.2 Hz), 7.91 (1H, d, J=8.4 Hz), 8.08 (1H,ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.20 (1H, dd, J=2.2 Hz, 8.6 Hz), 8.31(1H, d, J=8.8 Hz), 8.63 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.70 (1H,d, J=2.2 Hz), 12.31 (1H, br s).

[1493] Elementary Analysis: for C₁₇H₁₄N₄O₃S.0.25H₂O

[1494] Calcd.: C, 56.89; H, 4.07; N, 15.61; S, 8.93.

[1495] Found: C, 56.84; H, 3.86; N, 15.63; S, 8.93.

EXAMPLE 2-53

[1496]4-Chloro-3-methyl-6-nitro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1497] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-5-nitrobenzoic acid(58% yield).

[1498] mp: 282° C. (recrystallized from chloroform).

[1499] NMR (CDCl₃) δ: 3.02 (3H, s), 7.31 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4Hz), 7.97 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.0 Hz), 8.28 (1H, d, J=9.6 Hz),8.56 (1H, dd, J=2.4 Hz, 9.6 Hz), 8.66-8.72 (2H, m), 9.38 (1H, d, J=2.4Hz).

[1500] Elementary Analysis: for C₁₆H₁₁ClN₅O₂

[1501] Calcd.: C, 56.56; H, 2.97; N, 20.61; Cl, 10.44.

[1502] Found: C, 56.49; H, 2.70; N, 20.64; Cl, 10.39.

EXAMPLE 2-54

[1503]3-Methyl-6-nitro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1504] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-6-nitro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(98% yield).

[1505] mp: >300° C.

[1506] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.40-7.46 (1H, m), 7.89 (1H, d,J=8.4 Hz), 8.03-8.12 (1H, m), 8.26 (1H, d, J=9.2 Hz), 8.47 (1H, dd,J=2.4 Hz, 9.2 Hz), 8.60-8.63 (1H, m), 8.91 (1H, d, J=2.4 Hz), 12.37 (1H,br s).

[1507] Elementary Analysis: for C₁₆H₁₁N₅O₃.0.25H₂O

[1508] Calcd.: C, 58.99; H, 3.56; N, 21.50.

[1509] Found: C, 58.71; H, 3.47; N, 21.55.

EXAMPLE 2-55

[1510]6-Amino-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1511] A solution of3-methyl-6-nitro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(4.64 g, 14.4 immol) and 5% palladium-carbon (4.64 g, 50% hydrate) inN,N-dimethylformamide (400 mL) was stirred at room temperature underhydrogen atmosphere for 4 hours. The reaction solution was filtered toremove the catalyst, and the filtrate was evaporated under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography (chloroform:methanol=99:1 to chloroform:methanol=95:5) togive the title compound (2.86 g, 69% yield).

[1512] mp: 260-262° C. (recrystallized from chloroform/methanol).

[1513] NMR (DMSO-d₆) δ: 2.61 (3H, s), 5.24 (2H, br s), 7.05 (1H, dd,J=2.6 Hz, 8.8 Hz), 7.33-7.39 (2H, m), 7.76 (1H, d, J=8.8 Hz), 7.87 (1H,d, J=8.4 Hz), 8.04 (1H, ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.57-8.61 (1H,m), 11.64 (1H, br s).

[1514] Elementary Analysis: for C₁₆H₁₃N₅O.0.1H₂O

[1515] Calcd.: C, 65.56; H, 4.54; N, 23.89.

[1516] Found: C, 65.41; H, 4.74; N, 23.86.

EXAMPLE 2-56

[1517]6-Dimethylamino-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1518] A solution of6-amino-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(1.00 g, 3.43 mmol), sodium cyanotrihydroborate (1.08 g, 17.2 mmol) andparaformaldehyde (1.00 g) in acetic acid (20 mL) was stirred at roomtemperature for 18 hours under an argon atmosphere. The reaction solventwas evaporated under reduced pressure, and the residue was poured intoiced water. After the solution was made basic by the addition of asodium hydroxide solution, the organic matter was extracted withchloroform. The extract was washed with saturated brine and water anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (chloroform to chloroform:methanol=99:1) togive the title compound (0.56 g, 51% yield).

[1519] mp: 171-173° C. (recrystallized from ethyl acetate/hexane).

[1520] NMR (CDCl₃) (: 2.76 (3H, s), 3.02 (6H, s), 7.14-7.21 (2H, m),7.35 (1H, d, J=8.8 Hz), 7.69 (1H, d, J=2.6 Hz), 7.85 (1H, ddd, J=1.8 Hz,7.0 Hz, 8.4 Hz), 7.98 (1H, ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz), 8.46 (1H,ddd, J=0.8 Hz, 1.8 Hz, 5.0 Hz), 11.24 (1H, br s).

[1521] Elementary Analysis: for C₁₈H₁₇N5O.H₂O

[1522] Calcd.: C, 64.08; H, 5.63; N, 20.76.

[1523] Found: C, 64.15; H, 5.78; N, 21.02.

EXAMPLE 2-57

[1524]4-Chloro-3-methyl-7-nitro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1525] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-4-nitrobenzoic acid(36% yield).

[1526] mp: 226-227° C. (recrystallized from ethyl acetate).

[1527] NMR (CDCl₃) δ: 3.03 (3H, s), 7.31 (1H, ddd, J=0.8 Hz, 4.8 Hz, 7.4Hz), 7.98 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.32 (1H, dd, J=2.2 Hz,9.2 Hz), 8.57 (1H, d, J=9.2 Hz), 8.69-8.76 (2H, m), 9.10 (1H, d, J=2.2Hz).

[1528] Elementary Analysis: for C₁₆H₁₀ClN₅O₂

[1529] Calcd.: C, 56.56; H, 2.97; N, 20.61; Cl, 10.44.

[1530] Found: C, 56.42; H, 2.74; N, 20.54; Cl, 10.32.

EXAMPLE 2-58

[1531]3-Methyl-7-nitro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1532] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-7-nitro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(96% yield).

[1533] mp: >300° C. (recrystallized from chloroform/methanol).

[1534] NMR (DMSO-d₆) δ: 2.62 (3H, s), 7.42 (1H, ddd, J=0.8 Hz, 4.8 Hz,7.4 Hz), 7.90 (1H, d, J=8.4 Hz), 8.01-8.12 (2H, m), 8.39 (1H, d, J=8.8Hz), 8.61 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 9.18 (1H, d, J=2.2 Hz),12.41 (1H, br s).

[1535] Elementary Analysis: for C₁₆H₁₁N₅O₃.0.25H₂O

[1536] Calcd.: C, 58.99; H, 3.56; N, 21.50.

[1537] Found: C, 58.90; H, 3.67; N, 21.72.

EXAMPLE 2-59

[1538]7-Amino-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1539] Following the procedure described in Example 2-55, the titlecompound was prepared from3-methyl-7-nitro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(58% yield).

[1540] mp: 284-286° C. (recrystallized from chloroform/methanol).

[1541] NMR (DMSO-d₆) δ: 2.57 (3H, s), 5.98 (2H, br s), 6.58 (1H, dd,J=2.2 Hz, 8.8 Hz), 6.87 (1H, d, J=2.2 Hz), 7.36 (1H, ddd, J=1.0 Hz, 4.8Hz, 7.4 Hz), 7.85-7.90 (2H, m), 8.04 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4Hz), 8.59 (1H, ddd, J=1.0 Hz, 1.8 Hz, 4.8 Hz), 11.43 (1H, br s).

[1542] Elementary Analysis: for C₁₆H₁₃N₅O.0.6H₂O

[1543] Calcd.: C, 63.61; H, 4.74; N, 23.18.

[1544] Found: C, 63.90; H, 4.70; N, 22.79.

EXAMPLE 2-60

[1545] Methyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-5-carboxylate

[1546] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from methyl4-oxo-2-(2-oxopropyl)-4H-3,1-benzoxazine-5-carboxylate and2-hydrazinopyridine (38% yield).

[1547] mp: 168-171° C. (recrystallized from ethyl acetate).

[1548] NMR (CDCl₃) δ: 3.00 (3H, s), 4.04 (3H, s), 7.23-7.30 (1H, m),7.65 (1H, dd, J=1.6 Hz, 7.0 Hz), 7.79 (1H, dd, J=7.0 Hz, 8.8 Hz),7.91-8.00 (1H, m), 8.28 (1H, dd, J=1.6 Hz, 8.8 Hz), 8.67-8.72 (1H, m),8.76-8.81 (1H, m).

[1549] Elementary Analysis: for C₁₈H₁₃ClN₄O

[1550] Calcd.: C, 61.28; H, 3.71; N, 15.88; Cl, 10.05.

[1551] Found: C, 61.48; H, 3.74; N, 16.07; Cl, 9.90.

EXAMPLE 2-61

[1552] Methyl3-methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-5-carboxylate

[1553] Following the procedure described in Example 2-13, the titlecompound was prepared from methyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-5-carboxylate(30% yield).

[1554] mp: 241-244° C. (recrystallized from ethyl acetate).

[1555] NMR (CDCl₃) δ: 2.73 (3H, s), 4.08 (3H, s), 7.20-7.25 (2H, m),7.47-7.53 (1H, m), 7.65 (1H, dd, J=6.8 Hz, 8.4 Hz), 7.86-7.95 (1H, m),8.01 (1H, d, J=8.4 Hz), 8.46-8.50 (1H, m), 11.58 (1H, s).

[1556] Elementary Analysis: for C₁₈H₁₄N₄O₃

[1557] Calcd.: C, 64.66; H, 4.22; N, 16.76.

[1558] Found: C, 61.90; H, 4.45; N, 16.78.

EXAMPLE 2-62

[1559]3-Methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-5-carboxylicacid

[1560] The basic aqueous layer described in Example 2-61 was made acidicby the addition of an aqueous hydrochloric acid solution, and theresulting precipitate was collected by filtration. The crude crystalswere washed with water and ethanol and dried to give the title compound(32% yield).

[1561] mp: 303-306° C. (recrystallized from chloroform/methanol).

[1562] NMR (DMSO-d₆) δ: 2.61 (3H, s), 7.22 (1H, d, J=7.0 Hz), 7.37-7.44(1H, m), 7.69-7.78 (1H, m), 7.91 (1H, d, J=8.2 Hz), 8.02-8.08 (1H, m),8.12 (1H, d, J=7.8 Hz), 8.63 (1H, d, J=4.4 Hz), 12.05 (1H, s), 12.85(1H, br s).

[1563] Elementary Analysis: for C₁₇H₁₂N₄O₃.0.2H₂O

[1564] Calcd.: C, 63.04; H, 3.86; N, 17.30.

[1565] Found: C, 63.13; H, 3.72; N, 17.44.

EXAMPLE 2-63

[1566] Methyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-6-carboxylate

[1567] Following the procedure described in Reference Example 2-5,4-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]isophthalic acid wasprepared from bromoisophthalic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (99% yield). A solution ofthe compound (23.0 g, 68.0 mmol) in phosphorus oxychloride (108 g, 704mmol) was heated under reflux for I hour. The reaction solution wasallowed to cool to room temperature, and the solvent was evaporatedunder reduced pressure. To a stirred mixture of the residue intetrahydrofuran (100 mL), methanol (10 mL) was added dropwise carefully,and the precipitate was collected by filtration. The precipitate wasdissolved in a sodium hydroxide solution, and organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (chloroform) to give thetitle compound (3.40 g, 14% yield).

[1568] mp: 199-200° C. (recrystallized from ethyl acetate).

[1569] NMR (CDCl₃) δ: 3.01 (3H, s), 4.04 (3H, s), 7.27 (1H, ddd, J=1.0Hz, 4.8 Hz, 7.4 Hz), 7.95 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.19 (1H,d, J=9.0 Hz), 8.38 (1H, dd, J=1.8 Hz, 9.0 Hz), 8.69 (1H, ddd, J=0.8 Hz,1.8 Hz, 4.8 Hz), 8.78 (1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz), 9.15 (1H, d,J=1.8 Hz).

[1570] Elementary Analysis: for C₁₈H₁₃ClN₄O₂

[1571] Calcd.: C, 61.28; H, 3.71; N, 15.88; Cl, 10.05.

[1572] Found: C, 61.19; H, 3.53; N, 15.71; Cl, 9,95.

EXAMPLE 2-64

[1573] Methyl3-methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-6-carboxylate

[1574] Following the procedure described in Example 2-13, the titlecompound was prepared from methyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-6-carboxylate(58% yield).

[1575] mp: 265-266° C. (recrystallized from ethyl acetate/methanol).

[1576] NMR (CDCl3) δ: 2.74 (3H, s), 3.96 (3H, s), 7.25 (1H, ddd, J=l1.2Hz, 5.2 Hz, 7.0 Hz), 7.46 (1H, d, J=8.4 Hz), 7.91 (1H, ddd, J=1.2 Hz,7.0 Hz, 8.4 Hz), 8.01 (1H, ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz), 8.27 (1H, dd,J=2.2 Hz, 8.4 Hz), 8.48 (1H, ddd, J=0.8 Hz, 2.0 Hz, 5.2 Hz), 9.11 (1H,d, J=2.2 Hz), 11.61 (1H, br s).

[1577] Elementary Analysis: for C₁₈H₁₄N₄O₃

[1578] Calcd.: C, 64.66; H, 4.22; N, 16.76.

[1579] Found: C, 64.56; H, 4.28; N, 16.72.

EXAMPLE 2-65

[1580]3-Methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-6-carboxylicacid

[1581] To a solution of methyl3-methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-6-carboxylate(0.96 g, 2.87 mmol) in ethanol (20 mL), was added 2N sodium hydroxide(20 mL), and the mixture was heated under reflux for 1 hour. Thesolution was allowed to cool to room temperature, and made acidic by theaddition of 1N hydrochloric acid, and the resulting precipitate wascollected by filtration. The crude crystals were recrystallized fromchloroform/methanol to give the title compound (0.87 g, 93% yield).

[1582] mp: >300° C. (recrystallized from chloroform/methanol).

[1583] NMR (DMSO-d₆) δ: 2.62 (3H, s), 4.10 (1H, br s), 7.42 (1H, ddd,J=1.0 Hz, 4.8 Hz, 7.2 Hz), 7.90 (1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz),8.07 (1H, ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.12 (1H, d, J=8.8 Hz), 8.20(1H, dd, J=1.8 Hz, 8.8 Hz), 8.62 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz),8.80 (1H, d, J=1.8 Hz), 12.16 (1H, br s).

[1584] Elementary Analysis: for C₁₇H₁₂N₄O₃.0.8H₂O

[1585] Calcd.: C, 61.00; H, 4.10; N, 16.74.

[1586] Found: C, 60.84; H, 4.00; N, 16.60.

EXAMPLE 2-66

[1587] Methyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-7-carboxylate

[1588] Following the procedure described in Example 2-63, the titlecompound was prepared from bromoterephthalic acid and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (24% yield).

[1589] mp: 239-240° C. (recrystallized from chloroform/hexane).

[1590] NMR (CDCl₃) δ: 3.00 (3H, s), 4.04 (3H, s), 7.23-7.30 (1H, m),7.95 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.13 (1H, dd, J=1.6 Hz, 8.8Hz), 8.43 (1H, d, J=8.8 Hz), 8.68 (1H, ddd, J=0.6 Hz, 1.8 Hz, 4.8 Hz),8.83 (1H, d, J=8.4 Hz), 8.87 (1H, d, J=1.6 Hz).

[1591] Elementary Analysis: for C₁₈H₁₃ClN₄O₂

[1592] Calcd.: C, 61.28; H, 3.71; N, 15.88; Cl, 10.05.

[1593] Found: C, 61.24; H, 3.83; N, 16.04; Cl, 9.98.

EXAMPLE 2-67

[1594] Methyl3-methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-7-carboxylate

[1595] Following the procedure described in Example 2-13, the titlecompound was prepared from methyl4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-7-carboxylate(34% yield).

[1596] mp: 251-252° C. (recrystallized from chloroform/methanol).

[1597] NMR (DMSO-d₆) δ: 2.61 (3H, s), 3.94 (3H, s), 7.40 (1H, ddd, J=1.2Hz, 5.2 Hz, 7.4 Hz), 7.79 (1H, dd, J=1.6 Hz, 8.4 Hz), 7.87 (1H, dd,J=1.2 Hz, 8.4 Hz), 8.05 (1H, ddd, J=l1.8 Hz, 7.4 Hz, 8.4 Hz), 8.28 (1H,d, J=8.4 Hz), 8.60 (1H, ddd, J=1.0 Hz, 1.8 Hz, 5.2 Hz), 8.80 (1H, d,J=1.6 Hz), 12.18 (1H, br s).

[1598] Elementary Analysis: for C₁₈H₁₄N₄O₃.H₂O

[1599] Calcd.: C, 61.36; H, 4.58; N, 15.90.

[1600] Found: C, 61.36; H, 4.51; N, 16.09.

EXAMPLE 2-68

[1601]3-Methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-7-carboxylicacid

[1602] Following the procedure described in Example 2-65, the titlecompound was prepared from methyl3-methyl-4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-7-carboxylate(74% yield).

[1603] mp: >300° C. (recrystallized from chloroform/methanol).

[1604] NMR (DMSO-d₆) δ: 2.62 (3H, s), 7.40 (1H, ddd, J=1.0 Hz, 4.8 Hz,7.4 Hz), 7.81 (1H, dd, J=1.4 Hz, 8.4 Hz), 7.88 (1H, d, J=8.4 Hz), 8.05(1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.28 (1H, d, J=8.4 Hz), 8.61 (1H,ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.79 (1H, d, J=1.4 Hz), 12.19 (1H, brs), hidden (1H).

[1605] Elementary Analysis: for C₁₇H₁₂N₄O₃.0.1H₂O

[1606] Calcd.: C, 63.39; H, 3.82; N, 17.39.

[1607] Found: C, 63.33; H, 3.89; N, 17.41.

EXAMPLE 2-69

[1608]5-Chloro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1609] Following the procedure described in Example 2-12, the titlecompound was prepared from6-chloro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(44% yield).

[1610] mp: 212-213° C. (recrystallized from ethanol).

[1611] NMR (DMSO-d₆) δ: 2.58 (3H, s), 7.28 (1H, dd, J=1.0 Hz, 7.8 Hz),7.40 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.2 Hz), 7.60 (1H, dd, J=7.8 Hz, 8.4Hz), 7.87 (1H, dd, J=1.0 Hz, 8.4 Hz), 8.02 (1H, dd, J=1.0 Hz, 8.4 Hz),8.02-8.10 (1H, m), 8.60 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 11.84 (1H,br s).

[1612] Elementary Analysis: for C₁₆H₁₁ClN₄O.0.5H₂O

[1613] Calcd.: C, 60.10; H, 3.78; N, 17.52; Cl, 11.09.

[1614] Found: C, 59.91; H, 3.77; N, 17.47; Cl, 10.91.

EXAMPLE 2-70

[1615] 4,6-Dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1616] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from6-chloro-2-(2-oxypropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine(5% yield).

[1617] mp: 233-235° C. (recrystallized from ethyl acetate/methanol).

[1618] NMR (CDCl₃) δ: 2.99 (3H, s), 7.22-7.29 (1H, m), 7.74 (1H, dd,J=2.6 Hz, 9.0 Hz), 7.89-7.98 (1H, m), 8.12 (1H, d, J=9.0 Hz), 8.37 (1H,d, J=2.2 Hz), 8.67-8.69 (1H, m), 8.75 (1H, d, J=8.0 Hz).

[1619] Elementary Analysis: for C₁₆H₁₀Cl₂N₄

[1620] Calcd.: C, 58.38; H, 3,06; N, 17.02; Cl, 21.54.

[1621] Found: C, 58.54; H, 3.06; N, 17.02; Cl, 21.48.

EXAMPLE 2-71

[1622]6-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1623] Following the procedure described in Example 2-2, the titlecompound was prepared from4,6-dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (61% yield).

[1624] mp: 289-292° C. (recrystallized from ethyl acetate/methanol).

[1625] NMR (DMSO-d₆) δ: 2.80 (3H, s), 7.38 (1H, dd, J=5.2 Hz, 6.6 Hz),7.80 (1H, dd, J=2.4 Hz, 8.8 Hz), 8.00-8.11 (2H, m), 8.29 (1H, d, J=8.0Hz), 8.40 (2H, s), 8.58 (1H, d, J=6.6 Hz), 8.73 (1H, d, J=2.4 Hz).

[1626] Elementary Analysis: for C₁₆H₁₂ClN₅.1.5H₂O

[1627] Calcd.: C, 57,06; H, 4.49; N, 20.80.

[1628] Found: C, 57.03; H, 4.11; N, 20.73.

EXAMPLE 2-72

[1629]6-Chloro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1630] Following the procedure described in Example 2-13, the titlecompound was prepared from4,6-dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (84%yield).

[1631] mp: 254-255° C. (recrystallized from ethanol).

[1632] NMR (DMSO-d₆) δ: 2.59 (3H, s), 7.37-7.44 (1H, m), 7.74 (1H, dd,J=2.6 Hz, 9.2 Hz), 7.88 (1H, d, J=8.4 Hz), 8.02-8.13 (3H, m), 8.59-8.61(1H, m), 12.05 (1H, br s).

[1633] Elementary Analysis: for C₁₆H₁₁ClN₄O

[1634] Calcd.: C, 61.84; H, 3.57; N, 18.03; Cl, 11.41.

[1635] Found: C, 61.80; H, 3.61; N, 18.16; Cl, 11.36.

EXAMPLE 2-73

[1636] 4,7-Dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1637] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from 4-chloro-2-iodobenzoicacid and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (23% yield).

[1638] mp: 203-204° C. (recrystallized from ethyl acetate).

[1639] NMR (CDCl₃) δ: 2.99 (3H, s), 7.26 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4Hz), 7.53 (1H, dd, J=1.8 Hz, 9.2 Hz), 7.94 (1H, ddd, J=1.8 Hz, 7.4 Hz,8.4 Hz), 8.18 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=9.2 Hz), 8.68 (1H, ddd,J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.77 (1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz).

[1640] Elementary Analysis: for C₁₆H₁₀Cl₂N₄

[1641] Calcd.: C, 58.38; H, 3.06; N, 17.02; Cl, 21.54.

[1642] Found: C, 58.32; H, 3.22; N, 16.99; Cl, 21.54.

EXAMPLE 2-74

[1643]7-Chloro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1644] Following the procedure described in Example 2-13, the titlecompound was prepared from4,7-dichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (92%yield).

[1645] mp: 274-275° C. (recrystallized from ethanol).

[1646] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.34 (1H, dd, J=1.8 Hz, 8.4 Hz),7.37-7.44 (1H, m), 7.89 (1H, d, J=8.4 Hz), 8.02-8.11 (1H, m), 8.19 (1H,d, J=8.4 Hz), 8.25 (1H, d, J=1.8 Hz), 8.58-8.61 (1H, m), 12.04 (1H, brs).

[1647] Elementary Analysis: for C₁₆H₁₁ClN₄O

[1648] Calcd.: C, 61.84; H, 3.57; N, 18.03; Cl, 11.41.

[1649] Found: C, 61.69; H, 3.76; N, 17.95; Cl, 11.31.

EXAMPLE 2-75

[1650]4,6,7-Trichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1651] Following the procedure described in Example 2-1, the titlecompound was prepared from4,5-dichloro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (45% yield).

[1652] mp: 213-214° C. (recrystallized from ethyl acetate).

[1653] NMR (CDCl₃) δ: 2.98 (3H, s), 7.23-7.30 (1H, m), 7.93 (1H, ddd,J=1.8 Hz, 7.6 Hz, 8.4 Hz), 8.30 (1H, s), 8.47 (1H, s), 8.67-8.72 (2H,m).

[1654] Elementary Analysis: for C₁₆H₉Cl₃N₄

[1655] Calcd.: C, 52.85; H, 2.49; N, 15.41; Cl, 29.25.

[1656] Found: C, 52.92; H, 2.44; N, 15.39; Cl, 29.10.

EXAMPLE 2-76

[1657]6,7-Dichloro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1658] Following the procedure described in Example 2-13, the titlecompound was prepared from4,6,7-trichloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(99% yield).

[1659] mp: 303-304° C. (recrystallized from ethanol).

[1660] NMR (DMSO-d₆) δ: 2.56 (3H, s), 7.40, (1H, ddd, J=0.8 Hz, 4.8 Hz,7.4 Hz), 7.86 (1H, d, J=8.4 Hz), 8.06 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4Hz), 8.18 (1H, s), 8.44 (1H, s), 8.56 (1H, ddd, J=0.6 Hz, 1.8 Hz, 4.8Hz), 12.06 (1H, br s).

[1661] Elementary Analysis: for C₁₆H₁₀Cl₂N₄O

[1662] Calcd.: C, 55.67; H, 2.92; N, 16.23; Cl, 20.54.

[1663] Found: C, 55.55; H, 2.74; N, 16.18; Cl, 20.54.

EXAMPLE 2-77

[1664]6,8-Dichloro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1665] Following the procedure described in Example 2-12, the titlecompound was prepared from3,5-dichloro-2-[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (65% yield).

[1666] mp: 288-289° C. (recrystallized from DMSO).

[1667] NMR (CDCl₃:CF₃CO₂D=50:1) δ: 2.75 (3H, s), 7.31-7.37 (1H, m), 7.81(1H, d, J=2.2 Hz), 7.97-8.00 (2H, m), 8.35 (1H, d, J=2.2 Hz), 8.53-8.57(1H, m), 11.32 (1H, br s).

[1668] Elementary Analysis: for C₁₆H₁₀Cl₂N₄O

[1669] Calcd.: C, 55.62; H, 2.92; N, 16.23.

[1670] Found: C, 55.48; H, 2.81; N, 16.18.

EXAMPLE 2-78

[1671]4-Chloro-5-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1672] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from 2-fluoro-6-iodobenzoicacid and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (51% yield).

[1673] mp: 160-161° C. (recrystallized from ethyl acetate).

[1674] NMR (CDCl₃) δ: 3.01 (3H, s), 7.14-7.29 (2H, m), 7.63-7.76 (1H,m), 7.88-8.01 (2H, m), 8.65-8.78 (2H, m).

[1675] Elementary Analysis: for C₁₆H₁₀ClFN₄

[1676] Calcd.: C, 61.45; H, 3.22; N, 17.92; Cl, 11.34; F, 6.08.

[1677] Found: C, 61.19; H, 3.43; N, 17.94; Cl, 11.23; F, 6.05.

EXAMPLE 2-79

[1678]5-Fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-onehydrochloride

[1679] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-5-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(80% yield).

[1680] mp: >380° C.

[1681] NMR (DMSO-d₆) δ: 2.58 (3H, s), 6.42-6.54 (1H, m), 7.09-7.29 (3H,m), 7.84-7.95 (1H, m), 8.44 (1H, dd, J=1.2 Hz, 4.8 Hz), 8.95 (1H, d,J=8.4 Hz), hidden (1H).

[1682] Elementary Analysis: for C₁₆H₁₁FN₄O.HCl

[1683] Calcd.: C, 58.10; H, 3.66; N, 16.94; F, 5.74.

[1684] Found: C, 58.44; H, 3.32; N, 16.83; F, 5.75.

EXAMPLE 2-80

[1685]4-Chloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1686] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from 5-fluoro-2-iodobenzoicacid and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (57% yield).

[1687] mp: 185-187° C. (recrystallized from ethyl acetate).

[1688] NMR (DMSO-d₆) δ: 3.00 (3H, s), 7.21-7.28 (1H, m), 7.62 (1H, ddd,J=3.0 Hz, 5.4 Hz, 9.4 Hz), 7.89-7.99 (2H, m), 8.19 (1H, dd, J=5.4 Hz,9.4 Hz), 8.69 (1H, d, J=3.6 Hz), 8.77 (1H, d, J=8.2 Hz).

[1689] Elementary Analysis: for C₁₆H₁₀ClFN₄O

[1690] Calcd.: C, 61.45; H, 3.22; N, 17.92; Cl, 11.34; F, 6.08.

[1691] Found: C, 61.60; H, 3.10; N, 17.62; Cl, 11.22; F, 5.80.

EXAMPLE 2-81

[1692]6-Fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1693] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(51% yield).

[1694] mp: 278-280° C. (recrystallized from ethanol/tetrahydrofuran).

[1695] NMR (CDCl₃) δ: 2.75 (3H, s), 7.16-7.27 (1H, m), 7.33-7.48 (2H,m), 7.87-8.14 (3H, m), 8.48 (1H, d, J=5.2 Hz), 11.51 (1H, s).

[1696] Elementary Analysis: for C₁₆H₁₁FN₄O

[1697] Calcd.: C, 65.30; H, 3.77; N, 19.04; F, 6.46.

[1698] Found: C, 65.32; H, 3.83; N, 18.99; F, 6.17.

EXAMPLE 2-82

[1699]4-Chloro-7-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1700] Following the procedure described in Example 2-1, the titlecompound was prepared from4-fluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(45% yield).

[1701] mp: 192-193° C. (recrystallized from ethyl acetate).

[1702] NMR (CDCl₃) δ: 2.98 (3H, s), 7.22-7.29 (1H, m), 7.34-7.43 (1H,m), 7.78 (1H, dd, J=2.2 Hz, 10.4 Hz), 7.89-7.98 (1H, m), 8.41 (1H, dd,J=6.0 Hz, 9.2 Hz), 8.67-8.70 (1H, m), 8.77 (1H, d, J=8.4 Hz).

[1703] Elementary Analysis: for C₁₆H₁₀ClFN₄

[1704] Calcd. : C, 61.45; H, 3.22; N, 17.92; Cl, 11.34; F, 6.08.

[1705] Found: C, 61.48; H, 3.20; N, 18.13; Cl, 11.14; F, 6.10.

EXAMPLE 2-83

[1706]7-Fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1707] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-7-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(73% yield).

[1708] mp: 260-261° C. (recrystallized from ethanol).

[1709] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.12-7.22 (1H, m), 7.41 (1H, ddd,J=1.2 Hz, 4.8 Hz, 7.4 Hz), 7.87-7.96 (2H, m), 8.06 (1H, ddd, J=1.8 Hz,7.4 Hz, 8.4 Hz), 8.24 (1H, dd, J=6.6 Hz, 8.8 Hz), 8.60 (1H, ddd, J=1.2Hz, 1.8 Hz, 4.8 Hz), 12.01 (1H, br s).

[1710] Elementary Analysis: for C₁₆H₁₁FN₄O

[1711] Calcd.: C, 65.30; H, 3.77; N, 19.04; F, 6.46.

[1712] Found: C, 65.34; H, 3.71; N, 19.15; F, 6.44.

EXAMPLE 2-84

[1713]4-Chloro-8-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1714] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from 3-fluoro-2-iodobenzoicacid and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (36% yield).

[1715] mp: 191° C. (recrystallized from ethyl acetate).

[1716] NMR (CDCl₃) δ: 3.01 (3H, s), 7.26 (1H, ddd, J=1.2 Hz, 4.8 Hz, 7.4Hz), 7.45-7.59 (2H, m), 7.97 (1H, ddd, J=1.2 Hz, 7.4 Hz, 8.4 Hz),8.15-8.23 (1H, m), 8.68 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.92 (1H,ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz).

[1717] Elementary Analysis: for C₁₆H₁₀ClFN₄

[1718] Calcd.: C, 61.45; H, 3.22; N, 17.92; Cl, 11.34; F, 6.08.

[1719] Found: C, 61.23; H, 3.33; N, 17.85; Cl, 11.21; F, 6.10.

EXAMPLE 2-85

[1720]8-Fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1721] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-8-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(82% yield).

[1722] mp: 241° C. (recrystallized from ethanol).

[1723] NMR (DMSO-d₆) δ: 2.56 (3H, s), 7.24-7.42 (2H, m), 7.67 (1H, ddd,J=1.4 Hz, 8.0 Hz, 11.0 Hz), 7.87 (1H, d, J=8.0 Hz), 7.97 (1H, d, J=8.0Hz), 8.07 (1H, ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.56-8.59 (1H, m), 11.45(1H, br s).

[1724] Elementary Analysis: for C₁₆H₁₁FN₄O

[1725] Calcd. : C, 65.30; H, 3.77; N, 19.04; F, 6.46.

[1726] Found: C, 65.10; H, 3.74; N, 18.95; F, 6.43.

EXAMPLE 2-86

[1727]6-Bromo-4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1728] Following the procedures described in Reference Examples 2-1 and2-3 and Example 2-1, the title compound was prepared from2-amino-5-bromobenzoic acid and 2-hydrazinopyridine (24% yield).

[1729] mp: 234-235° C. (recrystallized from ethyl acetate/methanol).

[1730] NMR (CDCl₃) δ: 2.98 (3H, s), 7.22-7.29 (1H, m), 7.83-7.99 (3H,m), 8.05 (1H, d, J=9.2 Hz), 8.67-8.70 (1H, m), 8.75 (1H, d, J=8.4 Hz).

[1731] Elementary Analysis: for C₁₆H₁₀BrClN₄

[1732] Calcd.: C, 51.43; H, 2.70; N, 15.00; Br, 21.39; Cl, 9.49.

[1733] Found: C, 51.20; H, 2.85; N, 15.12; Br, 21.22; Cl, 9.37.

EXAMPLE 2-87

[1734]6-Bromo-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1735] Following the procedure described in Example 2-13, the titlecompound was prepared from6-bromo-4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(92% yield).

[1736] mp: 240-242° C. (recrystallized from ethanol/tetrahydrofuran).

[1737] NMR (CDCl₃) δ: 2.74 (3H, s), 7.20-7.24 (1H, m), 7.33 (1H, d,J=8.8 Hz), 7.71 (1H, dd, J=1.8 Hz, 8.4 Hz), 7.86-7.95 (1H, m), 8.01 (1H,d, J=8.4 Hz), 8.48 (1H, d, J=5.8 Hz), 8.56 (1H, d, J=1.8 Hz), 11.51 (1H,br s).

[1738] Elementary Analysis: for C₁₆H₁₁BrN₄O.0.5H₂O

[1739] Calcd.: C, 52.77; H, 3.32; N, 15.38; Br, 21.94.

[1740] Found: C, 52.81; H, 3.36; N, 15.09; Br, 21.92.

EXAMPLE 2-88

[1741]4-Chloro-5,6-difluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1742] Following the procedure described in Example 2-1, the titlecompound was prepared from5,6-difluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (78% yield).

[1743] mp: 240-242° C. (recrystallized from ethyl acetate).

[1744] NMR (CDCl₃) δ: 3.01 (3H, s), 7.22-7.31 (1H, m), 7.60-7.76 (1H,m), 7.88-8.03 (2H, m), 8.67-8.72 (2H, m).

[1745] Elementary Analysis: for C₁₆H₉ClF₂N₄

[1746] Calcd.: C, 58.11; H, 2.74; N, 16.94; Cl, 10.72; F, 11.49.

[1747] Found: C, 58.17; H, 2.93; N, 17.11; Cl, 10.56; F, 11.56.

EXAMPLE 2-89

[1748]5,6-Difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1749] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-5,6-difluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(86% yield).

[1750] mp: 300-303° C. (recrystallized from ethanol).

[1751] NMR (DMSO-d₆) δ: 3.34 (3H, s), 7.36-7.43 (1H, m), 7.71-7.94 (3H,m), 8.00-8.10 (1H, m), 8.56-8.60 (1H, m), 11.91 (1H, s).

[1752] Elementary Analysis: for C₁₆H₁₀F₂N₄O

[1753] Calcd.: C, 61.54; H, 3.23; N, 17.94; F, 12.17.

[1754] Found: C, 61.60; H, 3.33; N, 18.24; F, 12.24.

EXAMPLE 2-90

[1755]4-Chloro-6,7-difluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1756] A solution of4,5-difluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (8.14 g, 24.6 mmol) in phosphorous oxychloride (13 mL, 138 mmol)was heated under reflux for 1.5 hours. The solution was cooled to roomtemperature and concentrated under reduced pressure, and the residue waspoured into iced water. The solution was neutralized by the addition ofa sodium hydroxide solution, and the organic matter was extracted withchloroform. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (chloroform) to give the title compound (4.42g, 54% yield).

[1757] mp: 175-176° C. (recrystallized from ethyl acetate).

[1758] NMR (CDCl₃) δ: 2.98 (3H, s), 7.23-7.30 (1H, m), 7.87-7.98 (2H,m), 8.13 (1H, dd, J=8.6 Hz, 10.8 Hz), 8.67-8.72 (2H, m).

[1759] Elementary Analysis: for C₁₆H₉ClF₂N₄

[1760] Calcd.: C, 58.11; H, 2.74; N, 16.94; Cl, 10.72; F, 11.49.

[1761] Found: C, 57.71; H, 2.77; N, 16.90; Cl, 10.50; F, 11.17.

EXAMPLE 2-91

[1762]6,7-Difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1763] To a solution of4-chloro-6,7-difluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(2.21 g, 6.68 mmol) in ethanol (120 mL), 6N hydrochloric acid (6 mL,36.0 mmol) was added and the mixture was heated under reflux for 3hours. The solution was allowed to cool to room temperature, and theresulting crystals were collected by filtration. The crystals werewashed with ethanol and air dried to give the title compound (2.08 g,99% yield).

[1764] mp: 274-277° C. (recrystallized from ethanol).

[1765] NMR (DMSO-d₆) δ: 2.57 (3H, s), 7.40 (1H, ddd, J=1.0 Hz, 5.2 Hz,7.4 Hz), 7.84-8.11 (3H, m), 8.17 (1H, dd, J=7.0 Hz, 12.4 Hz), 8.57-8.60(1H, m), 12.04 (1H, s).

[1766] Elementary Analysis: for C₁₆H₁₀F₂N₄O

[1767] Calcd.: C, 61.54; H, 3.23; N, 17.94; F, 12.17.

[1768] Found: C, 61.45; H, 3.00; N, 17.77; F, 12.20.

EXAMPLE 2-92

[1769]6,7-Difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-onemonohydrate

[1770] A suspension of6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one(20.00 g, 64 mmol) in ethanol (200 mL) and water (200 mL) was heatedunder reflux for 6 hours. The suspension was allowed to cool to roomtemperature, and the resulting crystals were collected by filtration.The crystals were washed with water and air dried to give the titlecompound (20.77 g, 98% yield).

[1771] mp: 273-275° C.

[1772] NMR (DMSO-d₆) δ: 2.57 (3H, s), 7.40 (1H, ddd, J=1.0 Hz, 5.2 Hz,7.4 Hz), 7.84-8.11 (3H, m), 8.17 (1H, dd, J=7.0 Hz, 12.4 Hz), 8.57-8.60(1H, m), 12.04 (1H, s).

[1773] Elementary Analysis: for C₁₆H₁₀F₂N₄O.H₂O

[1774] Calcd.: C, 58.18; H, 3.66; N, 16.96; F, 11.50.

[1775] Found: C, 58.40; H, 3.74; N, 17.09; F, 11.49.

EXAMPLE 2-93

[1776]6,7-Difluoro-3-methyl-9-propyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1777] Following the procedure described in Example 2-16, the titlecompound was prepared from6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand 1-iodopropane (11% yield).

[1778] mp: 198-200° C. (recrystallized from ethyl acetate/hexane).

[1779] NMR (CDCl₃) δ: 0.55 (3H, t, J=7.6 Hz), 1.52-1.70 (2H, m), 2.72(3H, s), 3.95 (2H, t, J=7.6 Hz), 7.26 (1H, dd, J=6.0 Hz, 12.2 Hz), 7.45(1H, ddd, J=1.2 Hz, 4.8 Hz, 7.4 Hz), 7.78 (1H, ddd, J=0.8 Hz, 1.2 Hz,8.0 Hz), 8.00 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.0 Hz), 8.31 (1H, dd, J=9.2Hz, 10.8 Hz), 8.58 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz).

[1780] Elementary Analysis: for C₁₉H₁₆F₂N₄O

[1781] Calcd.: C, 64.40; H, 4.55; N, 15.81; F, 10.72.

[1782] Found: C, 64.34; H, 4.35; N, 15.67; F, 10.75.

EXAMPLE 2-94

[1783]6,7-Difluoro-3-methyl-4-propoxy-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1784] Following the procedure described in Example 2-16, from6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand 1-iodopropane was prepared the title compound (27% yield).

[1785] mp: 162-163° C. (recrystallized from ethyl acetate/hexane).

[1786] NMR (CDCl₃) δ: 1.20 (3H, t, J=7.4 Hz), 1.97-2.14 (2H, m), 2.90(3H, s), 4.31 (2H, t, J=6.8 Hz), 7.23 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4Hz), 7.82-8.00 (3H, m), 8.67 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.78(1H, ddd, J=0.8 Hz, 1.0 Hz, 8.2 Hz).

[1787] Elementary Analysis: for C₁₉H₁₆F₂N₄O

[1788] Calcd.: C, 64.40; H, 4.55; N, 15.81; F, 10.72.

[1789] Found: C, 64.49; H, 4.51; N, 15.80; F, 10.58.

EXAMPLE 2-95

[1790]6,7-Difluoro-4-isopropoxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1791] Following the procedure described in Example 2-16, the titlecompound was prepared from6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-oneand 2-iodopropane (42% yield).

[1792] mp: 159-160° C. (recrystallized from ethyl acetate).

[1793] NMR (CDCl₃) δ: 1.48 (6H, d, J=6.2 Hz), 2.90 (3H, s), 4.76-4.89(1H, m), 7.20-7.27 (1H, m), 7.82-8.00 (3H, m), 8.67 (1H, dd, J=1.0 Hz,4.8 Hz), 8.79 (1H, d, J=8.6 Hz).

[1794] Elementary Analysis: for C₁₉H₁₆F₂N₄O

[1795] Calcd.: C, 64.40; H, 4.55; N, 15.81.

[1796] Found: C, 64.33; H, 4.39; N, 15.75.

EXAMPLE 2-96

[1797]4,7-Dichloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1798] Following the procedure described in Example 2-1, the titlecompound was prepared from4-chloro-5-fluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (22% yield).

[1799] mp: 214-215° C. (recrystallized from ethyl acetate).

[1800] NMR (CDCl₃) δ: 2.97 (3H, s), 7.22-7.29 (1H, m), 7.89-7.98 (1H,m), 8.07 (1H, d, J=10.0 Hz), 8.26 (1H, d, J=6.8 Hz), 8.66-8.73 (2H, m).

[1801] Elementary Analysis: for C₁₆H₉Cl₂FN₄

[1802] Calcd.: C, 55.35; H, 2.61; N, 16.14.

[1803] Found: C, 55.37; H, 2.60; N, 15.86.

EXAMPLE 2-97

[1804]7-Chloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1805] Following the procedure described in Example 2-13, the titlecompound was prepared from4,7-dichloro-6-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(61% yield).

[1806] mp: 264-265° C. (recrystallized from ethanol).

[1807] NMR (DMSO-d₆) δ: 2.56 (3H, s), 7.37-7.43 (1H, m), 7.83-7.94 (2H,m), 8.06 (1H, dt, J=1.0 Hz, 7.9 Hz), 8.41 (1H, d, J=6.6 Hz), 8.57 (1H,d, J=4.8 Hz), 12.03 (1H, br s).

[1808] Elementary Analysis: for C₁₆H₁₀ClFN₄O.0.25H₂O

[1809] Calcd.: C, 57.67; H, 3.18; N, 16.81.

[1810] Found: C, 57.66; H, 3.23; N, 16.86.

EXAMPLE 2-98

[1811]4,6-Dichloro-7-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1812] Following the procedure described in Example 2-1, the titlecompound was prepared from5-chloro-4-fluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (58% yield).

[1813] mp: 211° C. (recrystallized from ethyl acetate).

[1814] NMR (CDCl₃) δ: 2.98 (3H, s), 7.23-7.30 (1H, m), 7.88 (1H, d,J=10.2 Hz), 7.94 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.46 (1H, d, J=7.6Hz), 8.67-8.72 (2H, m).

[1815] Elementary Analysis: for C₁₆H₉Cl₂FN₄

[1816] Calcd.: C, 55.35; H, 2.61; N, 16.14; Cl, 20.42; F, 5.47.

[1817] Found: C, 55.33; H, 2.35; N, 16.15; Cl, 20.31; F, 5.35.

EXAMPLE 2-99

[1818]6-Chloro-7-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1819] Following the procedure described in Example 2-13, the titlecompound was prepared from4,6-dichloro-7-fluoro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(79% yield).

[1820] mp: 284° C. (recrystallized from ethanol).

[1821] NMR (DMSO-d₆) δ: 2.54 (3H, s), 7.40 (1H, ddd, J=1.0 Hz, 4.8 Hz,7.4 Hz), 7.84 (1H, d, J=8.4 Hz), 8.05 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4Hz), 8.09 (1H, d, J=9.0 Hz), 8.14 (1H, d, 6.6 Hz), 8.56 (1H, ddd, J=0.8Hz, 1.8 Hz, 4.8 Hz), 12.02 (1H, br s).

[1822] Elementary Analysis: for C₁₆H₁₀ClFN₄O

[1823] Calcd.: C, 58.46; H, 3.07; N, 17.04; Cl, 10.78; F, 5.78.

[1824] Found: C, 58.38; H, 2.97; N, 17.14; Cl, 10.76; F, 5.76.

EXAMPLE 2-100

[1825] 3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1826] To a solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g,3.39 mmol) in ethanol (30 mL), 5% palladium-carbon (0.8 g, 50% hydrate)was added and the mixture was stirred at room temperature under hydrogenatmosphere for 1 hour. The solution was filtered to remove the catalyst,and the filtrate was concentrated under reduced pressure, and theresidue thus obtained was purified by silica gel column chromatography(ethyl acetate:hexane=6:4) to give the title compound (380 mg, 43%yield).

[1827] mp: 153-154° C. (recrystallized from ethyl acetate/hexane).

[1828] NMR (CDCl₃) δ: 2.82 (3H, s), 7.18-7.25 (1H, m), 7.48-7.56 (1H,m), 7.76-7.85 (1H, m), 7.89-8.05 (2H, m), 8.21 (1H, d, J=8.4 Hz), 8.59(1H, s), 8.65-8.70 (1H, m), 8.94 (1H, d, J=8.4 Hz).

EXAMPLE 2-101

[1829] 3,4-Dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1830] A solution of o-bromoacetophenone (1.09 g, 5.5 mmol),3-methyl-1-phenyl-1H-pyrazol-5-ylamine (0.87 g, 5.0 mmol), copperacetate (II) (91 mg, 0.5 mmol) and potassium carbonate (0.76 g, 5.5mmol) in N,N-dimethylformamide (5 mL) was heated under reflux under anargon atmosphere for 1 hour. The solution was cooled to roomtemperature, and poured into water. The solution was made basic by theaddition of a sodium bicarbonate solution, and the organic matter wasextracted with ethyl acetate. The extract was washed with saturatedbrine and water, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue thus obtainedwas purified by silica gel column chromatography (hexane:ethylacetate=1:1) to give the title compound (0.21 g, 15% yield).

[1831] mp: 157-159° C. (recrystallized from ethyl acetate/diethylether).

[1832] NMR (CDCl₃) δ: 2.97 (3H, s), 3.13 (3H, s), 7.17-7.24 (1H, m),7.48-7.57 (1H, m), 7.73-7.82 (1H, m), 7.88-7.98 (1H, m), 8.14-8.24 (2H,m), 8.65-8.69 (1H, m), 8.96 (1H, d, J=8.6 Hz).

[1833] Elementary Analysis: for C₁₇H₁₄N₄

[1834] Calcd.: C, 74.43; H, 5.14; N, 20.42.

[1835] Found: C, 74.28; H, 5.13; N, 20.56.

EXAMPLE 2-102

[1836] 4-Ethyl-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1837] To an ice-cold solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.95 g,10.0 mmol) in tetrahydrofuran (100 mL), a solution of 3M ethylmagnesiumbromide in diethyl ether (4.00 mL, 12.0 mmol) was added dropwise underan argon atmosphere, and the solution was stirred at the sametemperature for 1 hour. The reaction mixture was poured into iced water,and the organic matter was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvents were evaporated under reduced pressure. The residuethus obtained was purified by basic silica gel column chromatography(hexane:ethyl acetate=2:1) to give the title compound (0.33 g, 11%yield).

[1838] mp: 112-114° C. (recrystallized from ethyl acetate/hexane).

[1839] NMR (CDCl₃) δ: 1.49 (3H, t, J=7.6 Hz), 2.96 (3H, s), 3.59 (2H, q,J=7.6 Hz), 7.20 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4 Hz), 7.52 (1H, ddd,J=1.4 Hz, 6.6 Hz, 8.8 Hz), 7.77 (1H, ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz),7.93 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.18 (1H, dd, J=1.4 Hz, 8.8Hz), 8.23 (1H, dd, J=1.4 Hz, 8.8 Hz), 8.67 (1H, ddd, J=0.8 Hz, 1.8 Hz,4.8 Hz), 8.97 (1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz).

[1840] Elementary Analysis: for C₁₈H₁₆N₄.0.25H₂O

[1841] Calcd.: C, 73.82; H, 5.68; N, 19.13.

[1842] Found: C, 73.67; H, 5.74; N, 19.24.

EXAMPLE 2-103

[1843] 3-Methyl-4-propyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1844] Following the procedure described in Example 2-102, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and asolution of 2M propylmagnesium chloride in diethylether (16% yield).

[1845] mp: 108-109° C. (recrystallized from ethyl acetate/hexane).

[1846] NMR (CDCl₃) δ: 1.16 (3H, t, J=7.4 Hz), 1.78-1.97 (2H, m), 2.95(3H, s), 3.50-3.58 (2H, m), 7.20 (1H, ddd, J=0.8 Hz, 4.8 Hz, 7.4 Hz),7.51 (1H, ddd, J=1.2 Hz, 6.6 Hz, 8.8 Hz), 7.77 (1H, ddd, J=1.2 Hz, 6.6Hz, 8.6 Hz), 7.93 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.15 (2H, m),8.67 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.97 (1H, td, J=0.8 Hz, 8.4Hz).

[1847] Elementary Analysis: for C₁₉H₁₈N₄

[1848] Calcd.: C, 75.47; H, 6.00; N, 18.53.

[1849] Found: C, 75.18; H, 5.84; N, 18.59.

EXAMPLE 2-104

[1850] 4-Butyl-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1851] Following the procedure described in Example 2-102, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and asolution of 2M butylmagnesium chloride in tetrahydrofuran (15% yield).

[1852] mp: 102-103° C. (recrystallized from ethyl acetate/hexane).

[1853] NMR (CDCl₃) δ: 1.04 (3H, t, J=7.2 Hz), 1.52-1.66 (2H, m),1.70-1.89 (2H, m), 2.95 (3H, s), 3.51-3.59 (2H, m), 7.20 (1H, ddd, J=1.2Hz, 4.8 Hz, 7.4 Hz), 7.51 (1H, ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz), 7.76 (1H,ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz), 7.93 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4Hz), 8.14-8.24 (2H, m), 8.66 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.97(1H, ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz).

[1854] Elementary Analysis: for C₂₀H₂₀N₄

[1855] Calcd.: C, 75.92; H, 6.37; N, 17.71.

[1856] Found: C, 75.74; H, 6.15; N, 17.82.

EXAMPLE 2-105

[1857] 4-Isobutyl-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1858] Following the procedure described in Example 2-102, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and asolution of 1M isobutylmagnesium bromide in tetrahydrofuran (11% yield).

[1859] mp: 87-88° C. (recrystallized from ethyl acetate/hexane).

[1860] NMR (CDCl₃) δ: 1.04 (6H, d, J=6.6 Hz), 2.13-2.27 (1H, m), 2.96(3H, s), 3.46 (2H, d, J=7.4 Hz), 7.21 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4Hz), 7.50 (1H, ddd, J=1.4 Hz, 6.6 Hz, 8.6 Hz), 7.77 (1H, ddd, J=1.4 Hz,6.6 Hz, 8.6 Hz), 7.93 (1H, ddd, J=1.8 Hz, 7.4 Hz, 8.4 Hz), 8.15-8.24(2H, m), 8.67 (1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 8.97 (1H, ddd, J=0.8Hz, 1.0 Hz, 8.4 Hz).

[1861] Elementary Analysis: for C₂₀H₂₀N₄.H₂O

[1862] Calcd.: C, 71.83; H, 6.63; N, 16.75.

[1863] Found: C, 71.92; H, 6.66; N, 16.80.

EXAMPLE 2-106

[1864] 3-Methyl-4-pentyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1865] Following the procedure described in Example 2-102, the titlecompound was prepared from4-chloro-3-methyl-1(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and asolution of 1M pentylmagnesium bromide in tetrahydrofuran (24% yield).

[1866] mp: 121-122° C. (recrystallized from ethyl acetate/hexane).

[1867] NMR (CDCl₃) δ: 0.95 (3H, t, J=7.0 Hz), 1.33-1.92 (6H, m), 2.95(3H, s), 3.50-3.59 (2H, m), 7.17-7.27 (1H, m), 7.48-7.57 (1H, m),7.72-7.82 (1H, m), 7.88-7.98 (1H, m), 8.14-8.24 (2H, m), 8.64-8.69 (1H,m), 8.95-9.00 (1H, m)

[1868] Elementary Analysis: for C₂₁H₂₂N₄

[1869] Calcd.: C, 76.33; H, 6.71; N, 16.96.

[1870] Found: C, 76.16; H, 6.89; N, 17.23.

EXAMPLE 2-107

[1871]3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-4-carbonitrile

[1872] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (5.89 g,20.0 mmol), potassium cyanide (2.04 g, 31.3 mmol) and 18-crown-6 (6.96g, 26.3 mmol) in tetrahydrofuran (90 mL) and acetonitrile (90 mL) washeated under reflux for 8 hours. The solution was allowed to cool toroom temperature, and poured into water. The solution was made weaklybasic by the addition of a sodium hydroxide solution, and extracted withchloroform. The extract was washed with saturated brine and dried overanhydrous sodium sulfate, and the solvents were evaporated under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography (chloroform) to give crude crystals. The crude crystalswere recrystallized from ethyl acetate to give the title compound (2.86g, 50% yield).

[1873] mp: 210-211° C. (recrystallized from ethyl acetate).

[1874] NMR (CDCl₃) δ: 3.04 (3H, s), 7.28-7.33 (1H, m), 7.70-7.78 (1H,m), 7.88-8.02 (2H, m), 8.29 (1H, d, J=8.8 Hz), 8.38 (1H, dd, J=0.8 Hz,7.6 Hz), 8.69-8.77 (2H, m).

[1875] Elementary Analysis: for C₁₇H₁₁N₅

[1876] Calcd.: C, 71.57; H, 3.89; N, 24.55.

[1877] Found: C, 71.44; H, 3.68; N, 24.49.

EXAMPLE 2-108

[1878]3-Methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-4-carboxamide

[1879] A solution of3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-4-carbonitrile(0.30 g, 1.1 mmol) and conc. sulfuric acid (1.0 mL) in acetic acid (6.0mL) was heated under reflux for 31.5 hours. The solution was allowed tocool to room temperature, and poured into iced water. The resultingsolution was neutralized with an aqueous sodium hydroxide solution, andextracted with chloroform. The extract was washed with saturated brineand dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was recrystallizedfrom methanol/isopropylether to give the title compound (0.14 g, 44%yield).

[1880] mp: >300° C. (recrystallized from methanol/isopropylether).

[1881] NMR (CDCl₃:CF₃CO₂D=50:1) δ: 2.80 (3H, s), 7.56-7.66 (1H, m),7.75-7.84 (1H, m), 8.00-8.09 (1H, m), 8.23 (2H, d, J=9.8 Hz), 8.42-8.51(1H, m), 8.63-8.72 (2H, m), hidden (2H).

[1882] Elementary Analysis: for C₁₇H₁₃N₅O

[1883] Calcd.: C, 67.32; H, 4.32; N, 23.09.

[1884] Found: C, 67.15; H, 4.34; N, 22.97.

EXAMPLE 2-109

[1885]4-Chloro-1-(6-chloro-2-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline

[1886] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(6-chloro-2-pyridinyl)-1H-pyrazole-5-yl]amino]benzoicacid (35% yield).

[1887] mp: 191-193° C. (recrystallized from ethyl acetate/methanol).

[1888] NMR (CDCl₃) δ: 2.99 (3H, s), 7.25-7.29 (1H, m), 7.58-7.66 (1H,m), 7.80-7.88 (1H, m), 7.91 (1H, d, J=8.0 Hz), 8.17 (1H, d, J=8.8 Hz),8.39-8.44 (1H, m), 8.83 (1H, dd, J=0.8 Hz, 8.0 Hz).

[1889] Elementary Analysis: for C₁₆H₁₀Cl₂N₄

[1890] Calcd.: C, 58.38; H, 3.06; N, 17.02; Cl, 21.54.

[1891] Found: C, 58.43; H, 3.07; N, 17.03; Cl, 21.54.

EXAMPLE 2-110

[1892]1-(6-Chloro-2-pyridinyl)-3-methyl-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1893] Following the procedure described in Example 2-31, the titlecompound was prepared from4-chloro-1-(6-chloro-2-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline(18% yield).

[1894] mp: 251-253° C. (recrystallized from methanol).

[1895] NMR (DMSO-d₆) δ: 2.61 (3H, s), 7.35 (1H, t, J=7.4 Hz), 7.52 (1H,d, J=7.4 Hz), 7.69-7.82 (2H, m), 7.89 (1H, d, J=8.0 Hz), 8.11 (1H, t,J=8,0 Hz), 8.22 (1H, d, J=8.6 Hz), 11.44 (1H, br s).

[1896] Elementary Analysis: for C₁₆H₁₁ClN₄O

[1897] Calcd.: C, 61.84; H, 3.57; N, 18.03; Cl, 11.41.

[1898] Found: C, 61.64; H, 3.62; N, 17.78; Cl, 11.18.

EXAMPLE 2-111

[1899]4-Chloro-1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline

[1900] Following the procedure described in Reference Example 2-4,1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazol-5-ylamine was prepared from6-ethoxy-2-hydrazinopyridine which was prepared from2-chloro-6-ethoxypyridine following the method described in ReferenceExample 2-2. Subsequently, following the methods described in ReferenceExample 2-5 and Example 2-1, the title compound was prepared fromo-iodobenzoic acid and1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazol-5-ylamine (36% yield).

[1901] mp: 212-215° C. (recrystallized from ethyl acetate/methanol).

[1902] NMR (DMSO-d₆) δ: 1.62 (3H, t, J=7.1 Hz), 2.75 (3H, s), 4.49 (2H,q, J=7.1 Hz), 6.66 (1H, dd, J=0.74 Hz, 8.1 Hz), 7.23 (1H, d, J=8.4 Hz),7.29-7.38 (1H, m), 7.52 (1H, d, J=7.0 Hz), 7.60-7.71 (1H, m), 7.77 (1H,t, J=8.1 Hz), 8.54 (1H, d, J=8.4 Hz).

EXAMPLE 2-112

[1903]1-(6-Ethoxy-2-pyridinyl)-3-methyl-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1904] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline(92% yield).

[1905] mp: 231-234° C. (recrystallized from ethanol/diethylether).

[1906] NMR (DMSO-d₆) δ: 1.62 (3H, t, J=7.0 Hz), 2.73 (3H, s), 4.47 (2H,q, J=7.0 Hz), 6.63 (1H, dd, J=0.73 Hz, 8.1 Hz), 7.16 (1H, d, J=7.7 Hz),7.25-7.34 (1H, m), 7.49 (1H, d, J=7.7 Hz), 7.57-7.66 (1H, m), 7.74 (1H,t, J=8.1 Hz), 8.43 (1H, d, J=8.1 Hz), 11.15 (1H, br s).

EXAMPLE 2-113

[1907]4-Chloro-1-(5-chloro-2-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline

[1908] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(5-chloro-2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(22% yield).

[1909] mp: 216-217° C. (recrystallized from ethyl acetate/methanol).

[1910] NMR (CDCl₃) δ: 2.97 (3H, s), 7.56-7.64 (1H, m), 7.78-7.91 (2H,m), 8.14 (1H, td, J=0.8 Hz, 8.0 Hz), 8.38 (1H, td, J=0.8 Hz, 8.8 Hz),8.60 (1H, dd, J=0.8 Hz, 2.4 Hz), 8.87 (1H, dd, J=0.8 Hz, 8.8 Hz).

[1911] Elementary Analysis: for C₁₆H₁₀Cl₂N₄

[1912] Calcd.: C, 58.38; H, 3.06; N, 17.02; Cl, 21.54.

[1913] Found: C, 58.28; H, 3.10; N, 16.94; Cl, 21.83.

EXAMPLE 2-114

[1914]1-(5-Chloro-2-pyridinyl)-3-methyl-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1915] Following the procedure described in Example 2-31, the titlecompound was prepared from4-chloro-1-(5-chloro-2-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline(60% yield).

[1916] mp: 262-263° C. (recrystallized from methanol).

[1917] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.34 (1H, t, J=7.6 Hz), 7.68-7.76(1H, m), 7.88 (1H, d, J=8.8 Hz), 8.00 (1H, t, J=8.4 Hz), 8.14 (1H, dd,J=2.6 Hz, 8.8 Hz), 8.21 (1H, d, J=7.0 Hz), 8.57 (1H, d, J=2.6 Hz), 11.74(1H, br s).

[1918] Elementary Analysis: for C₁₆H₁₁ClN₄O.0.3H₂O

[1919] Calcd.: C, 60.79; H, 3.70; N, 17.72; Cl, 11.21.

[1920] Found: C, 60.91; H, 3.82; N, 17.71; Cl, 11.04.

EXAMPLE 2-115

[1921]4-Chloro-3-methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1922] Following the procedure described in Example 2-29, the titlecompound was prepared from anthranilic acid and2-hydrazino-5-methylpyridine which was previously prepared from2-bromo-5-methylpyridine (22% yield).

[1923] mp: 197-200° C. (recrystallized from ethyl acetate/methanol).

[1924] NMR (CDCl₃) δ: 2.42 (3H, s), 3.00 (3H, s), 7.53-7.64 (1H, m),7.71-7.87 (2H, m), 8.16 (1H, d, J=8.8 Hz), 8.36-8.43 (1H, m) , 8.46-8.52(1H, m) , 8.66 (1H, d, J=8.8 Hz).

[1925] Elementary Analysis: for C₁₇H₁₃ClN₄

[1926] Calcd.: C, 66.13; H, 4.24; N, 18.15.

[1927] Found: C, 66.16; H, 4.30; N, 18.10.

EXAMPLE 2-116

[1928]3-Methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1929] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3-methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (52% yield).

[1930] mp: 229-232° C. (recrystallized from ethyl acetate/methanol).

[1931] NMR (CDCl₃) δ: 2.38 (3H, s), 2.87 (3H, s), 5.60 (2H, br s),7.25-7.38 (1H, m), 7.62-7.74 (2H, m), 7.84 (1H, d, J=8.8 Hz), 8.00 (1H,d, J=8.8 Hz), 8.44 (1H, s), 8.75 (1H, d, J=8.4 Hz).

[1932] Elementary Analysis: for C₁₇H₁₅N₅

[1933] Calcd.: C, 70.57; H, 5.23; N, 24.21.

[1934] Found: C, 70.37; H, 5.51; N, 23.97.

EXAMPLE 2-117

[1935]3-Methyl-1-(5-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-onehydrochloride

[1936] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(51% yield).

[1937] mp: 227-229° C. (recrystallized from ethanol).

[1938] NMR (DMSO-d₆) δ: 2.38 (3H, s), 2.61 (3H, s), 7.33 (1H, t, J=7.5Hz), 7.66-7.92 (3H, m), 8.03 (1H, d, J=8.4 Hz), 8.22 (1H, d, J=7.0 Hz) ,8.43 (1H, s) , 11.85 (1H, s).

[1939] Elementary Analysis: for C₁₇H₁₄N₄.HCl.0.5H₂O

[1940] Calcd.: C, 60.81; H, 4.80; N, 16.68.

[1941] Found: C, 60.65; H, 5.25; N, 16.66.

EXAMPLE 2-118

[1942]4-Chloro-3-methyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1943] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazino-3-methylpyridine(21% yield).

[1944] mp: 160-161° C. (recrystallized from ethyl acetate/hexane).

[1945] NMR (CDCl₃) δ: 2.37 (3H, s), 2.98 (3H, s), 7.37 (1H, dd, J=4.8Hz, 7.6 Hz), 7.52-7.60 (1H, m), 7.72-7.83 (2H, m), 8.05 (1H, td, J=0.8Hz, 8.8 Hz), 8.39-8.44 (1H, m), 8.54-8.57 (1H, m).

[1946] Elementary Analysis: for C₁₇H₁₃ClN₄

[1947] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[1948] Found: C, 66.13; H, 4.28; N, 18.12; Cl, 11.51.

EXAMPLE 2-119

[1949] 3-Methyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1950] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3-methyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (63% yield).

[1951] mp: 202-205° C. (recrystallized from ethanol).

[1952] NMR (CDCl₃) δ: 2.35 (3H, s), 2.72 (3H, s), 5.67 (2H, br s),7.20-7.33 (2H, m), 7.53-7.63 (1H, m), 7.69-7.76 (1H, m), 7.79-7.89 (2H,m), 8.51 (1H, dd, J=1.5 Hz, 4.8 Hz).

[1953] Elementary Analysis: for C₁₇H₁₅N₅

[1954] Calcd.: C, 70.57; H, 5.23; N, 24.21.

[1955] Found: C, 70.53; H, 5.35; N, 23.96.

EXAMPLE 2-120

[1956]3-Methyl-1-(3-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1957] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(49% yield).

[1958] mp: 184-185° C. (recrystallized from ethanol).

[1959] NMR (DMSO-d₆) δ: 2.43 (3H, s), 2.60 (3H, s), 7.26-7.34 (1H, m),7.51 (1H, dd, J=4.8 Hz, 7.6 Hz), 7.62-7.76 (2H, m), 7.96-8.01 (1H, m),8.21-8.25 (1H, m), 8.51 (1H, dd, J=1.6 Hz, 4.8 Hz), 11.78 (1H, br s).

[1960] Elementary Analysis: for C₁₇H₁₄N₄O.1.2H₂O

[1961] Calcd.: C, 65.46; H, 5.30; N, 17.96.

[1962] Found: C, 65.47; H, 5.07; N, 17.81.

EXAMPLE 2-121

[1963]4-Chloro-3,5-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1964] Following the procedure described in Example 2-29, the titlecompound was prepared from 2-amino-6-methylbenzoic acid and6-ethoxy-2-hydrazinopyridine which was previously prepared from2-chloro-6-ethoxypyridine (32% yield).

[1965] mp: 146-148° C. (recrystallized from ethyl acetate).

[1966] NMR (CDCl₃) δ: 1.48 (3H, t, J=7.0 Hz), 2.96 (3H, s), 3.13 (3H,s), 4.57 (2H, q, J=7.0 Hz), 6.69 (1H, d, J=8.1 Hz), 7.31 (1H, d, J=7.0Hz), 7.63 (1H, t, J=7.0 Hz), 7.78 (1H, t, J=7.7 Hz), 7.96 (1H, d, J=7.7Hz), 8.12 (1H, d, J=8.1 Hz).

[1967] Elementary Analysis: for C₁₉H₁₇ClN₄O

[1968] Calcd.: C, 64.68; H, 4.86; N, 15.88.

[1969] Found: C, 64.62; H, 4.81; N, 16.10.

EXAMPLE 2-122

[1970]3,5-Dimethyl-1-(6-ethoxy-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1971] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3,5-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(90% yield).

[1972] mp: 213-215° C. (recrystallized from chloroform).

[1973] NMR (CDCl₃) δ: 1.61 (3H, t, J=7.0 Hz), 2.70 (3H, s), 2.97 (3H,s), 4.45 (2H, q, J=7.0 Hz), 6.62 (1H, dd, J=0.7 Hz, 8.1 Hz), 6.98 (2H,t, J=7.7 Hz), 7.39 (1H, d, J=7.7 Hz), 7.47 (1H, d, J=8.1 Hz), 7.74 (1H,t, J=8.1 Hz), 10.93 (1H, s).

[1974] Elementary Analysis: for C₁₉H₁₈N₄O₂.0.5H₂O

[1975] Calcd.: C, 66.46; H, 5.58; N, 16.32.

[1976] Found: C, 67.06; H, 5.43; N, 16.32.

EXAMPLE 2-123

[1977]4-Chloro-3,5-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1978] Following the procedure described in Example 2-29, the titlecompound was prepared from 2-amino-6-methylbenzoic acid and2-hydrazino-3-methylpyridine (38% yield).

[1979] mp: 176-178° C. (recrystallized from methanol/ethyl acetate).

[1980] NMR (CDCl₃) δ: 2.37 (3H, s), 2.97 (3H, s), 3.14 (3H, s),7.23-7.30 (1H, m), 7.35 (1H, dd, J=4.8 Hz, 7.7 Hz), 7.54 (1H, dd, J=7.0Hz, 8.8 Hz), 7.75-7.83 (1H, m), 7.85-7.93 (1H, m), 8.51-8.58 (1H, m).

[1981] Elementary Analysis: for C₁₈H₁₅ClN₄

[1982] Calcd.: C, 66.98; H, 4.68; N, 17.36.

[1983] Found: C, 66.94; H, 4.52; N, 17.51.

EXAMPLE 2-124

[1984]3,5-Dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[1985] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,5-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (65% yield).

[1986] mp: 271-274° C. (recrystallized from methanol/chloroform).

[1987] NMR (CDCl₃) δ: 2.36 (3H, s), 2.77 (3H, s), 2.99 (3H, s), 5.83(2H, br s), 6.95 (1H, d, J=7.0 Hz), 7.25-7.44 (2H, m), 7.64-7.78 (2H,m), 8.48-8.55 (1H, m).

[1988] Elementary Analysis: for C₁₈H₁₇N₅

[1989] Calcd.: C, 71.27; H, 5.65; N, 23.09.

[1990] Found: C, 70.89;. H, 5.56; N, 22.96.

EXAMPLE 2-125

[1991]3,5-Dimethyl-1-(3-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[1992] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3,5-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(73% yield).

[1993] mp: 195-197° C. (recrystallized from ethanol).

[1994] NMR (CDCl₃) δ: 2.71 (3H, s), 2.72 (3H, s), 2.99 (3H, s),6.98-7.05 (1H, m), 7.28-7.49 (3H, m), 7.80-7.88 (1H, m), 8.39-8.45 (1H,m), 11.50 (1H, br s).

[1995] Elementary Analysis: for C₁₈H₁₆N₄O.2H₂O

[1996] Calcd.: C, 63.52; H, 5.92; N, 16.46.

[1997] Found: C, 63.77; H, 5.11; N, 16.50.

EXAMPLE 2-126

[1998]4-Chloro-3,8-dimethyl-1-(6-methoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[1999] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methyl-2-(2-oxypropyl)-4H-3,1-benzoxazin-4-one and2-hydrazino-6-methoxypyridine which was previously prepared from and2-chloro-6-methoxypyridine following the method described in ReferenceExample 2-2 (75% yield).

[2000] mp: 148-151° C. (recrystallized from chloroform/hexane).

[2001] NMR (CDCl₃) δ: 2.87 (3H, s), 2.97 (3H, s), 4.15 (3H, s), 6.69(1H, d, J=8.1 Hz), 7.47 (1H, dd, J=6.8 Hz, 8.6 Hz), 7.64-7.71 (1H, m),7.80 (1H, t, J=8.1 Hz), 8.20-8.30 (2H, m).

[2002] Elementary Analysis: for C₁₈H₁₅ClN₄O

[2003] Calcd.: C, 63.81; H, 4.46; N, 16.54.

[2004] Found: C, 63.87; H, 4.44; N, 16.46.

EXAMPLE 2-127

[2005]3,8-Dimethyl-1-(6-methoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2006] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(6-methoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (46% yield).

[2007] mp: 134-137° C. (recrystallized from ethyl acetate/hexane).

[2008] NMR (CDCl₃) δ: 2.80 (3H, s), 2.86 (3H, s), 4.13 (3H, s), 5.50(2H, br s), 6.63 (1H, d, J=8.1 Hz), 7.20-7.30 (1H, m), 7.56 (1H, d,J=6.6 Hz), 7.70 (1H, d, J=6.6 Hz), 7.78 (1H, t, J=8.1 Hz), 8.44 (1H, d,J=7.7 Hz).

[2009] Elementary Analysis: for C₁₈H₁₇N₅O.H₂O

[2010] Calcd.: C, 64.08; H, 5.68; N, 20.76.

[2011] Found: C, 64.17; H, 5.43; N, 20.36.

EXAMPLE 2-128

[2012]4-Chloro-3,8-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2013] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and6-ethoxy-2-hydrazinopyridine which was previously prepared from2-chloro-6-ethoxypyridine following the method described in ReferenceExample 2-2 (62% yield).

[2014] mp: 151-153° C. (recrystallized from ethyl acetate).

[2015] NMR (CDCl₃) δ: 1.46 (3H, t, J=7.1 Hz), 2.86 (3H, s), 2.96 (3H,s), 4.60 (2H, q, J=7.1 Hz), 6.66 (1H, dd, J=0.73 Hz, 8.1 Hz), 7.46 (1H,q, J=7.0 Hz), 7.63-7.70 (1H, m), 7.79 (1H, t, J=8.1 Hz), 8.15-8.28 (2H,m).

[2016] Elementary Analysis: for C₁₉H₁₇ClN₄O

[2017] Calcd.: C, 64.68; H, 4.86; N, 15.88; Cl, 10.05.

[2018] Found: C, 64.54; H, 5.07; N, 15.69; Cl, 10.04.

EXAMPLE 2-129

[2019]3,8-Dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2020] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (82% yield).

[2021] mp: 184-187° C. (recrystallized from chloroform).

[2022] NMR (CDCl₃) δ: 1.45 (3H, t, J=7.0 Hz), 2.81 (3H, s), 2.87 (3H,s), 4.56 (2H, q, J=7.0 Hz), 5.47 (2H, br s), 6.61 (1H, d, J=8.0 Hz),7.25 (1H, q, J=7.0 Hz), 7.57 (1H, d, J=7.0 Hz), 7.70 (1H, d, J=8.0 Hz),7.79 (1H, t, J=8.0 Hz), 8.43 (1H, d, J=8.0 Hz).

[2023] Elementary Analysis: for C₁₉H₁₉N₅O

[2024] Calcd.: C, 68.45; H, 5.74; N, 21.01.

[2025] Found: C, 68.33; H, 6.00; N, 20.95.

EXAMPLE 2-130

[2026]3,8-Dimethyl-1-(6-ethoxy-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2027] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(6-ethoxy-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(73% yield).

[2028] mp: 239-241° C. (recrystallized from chloroform).

[2029] NMR (CDCl₃) δ: 1.51 (3H, t, J=7.0 Hz), 2.52 (3H, s), 2.72 (3H,s), 4.40 (2H, q, J=7.0 Hz), 6.60 (1H, dd, J=0.74 Hz, 8.1 Hz), 7.18 (1H,t, J=8.1 Hz), 7.40-7.48 (1H, m), 7.53 (1H, dd, J=0.74 Hz, 8.1 Hz), 7.73(1H, t, J=8.1 Hz), 8.30 (1H, d, J=7.3 Hz), 10.9 (1H, br s).

[2030] Elementary Analysis: for C₁₉H₁₈N₄O₂

[2031] Calcd.: C, 68.25; H, 5.43; N, 16.76.

[2032] Found: C, 68.08; H, 5.59; N, 16.60.

EXAMPLE 2-131

[2033]4-Chloro-3,8-dimethyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2034] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazino-5-methylpyridine which was previously prepared from2-bromo-5-methylpyridine following the method described in ReferenceExample 2-2 (62% yield).

[2035] mp: 165-168° C. (recrystallized from methanol/ethyl acetate).

[2036] NMR (CDCl₃) δ: 2.42 (3H, s), 2.85 (3H, s), 2.99 (3H, s), 7.46(1H, dd, J=7.7 Hz, 8.4 Hz), 7.62-7.72 (1H, m), 7.75 (1H, m), 8.23 (1H,m), 8.48 (1H, m), 8.88 (1H, d, J=8.4 Hz).

[2037] Elementary Analysis: for C₁₈H₁₅ClN₄

[2038] Calcd.: C, 66.98; H, 4.68; N, 17.36.

[2039] Found: C, 66.93; H, 4.59; N, 17.23.

EXAMPLE 2-132

[2040]3,8-Dimethyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2041] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(5-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (43% yield).

[2042] mp: 257-260° C. (recrystallized from ethyl acetate).

[2043] NMR (CDCl₃) δ: 2.39 (3H, s), 2.78 (3H, s), 2.87 (3H, s), 5.48(2H, br s), 7.18-7.30 (1H, m), 7.55 (1H, d, J=6.6 Hz), 7.65-7.75 (2H,m), 8.43 (1H, s), 9.02 (1H, d, J=8.1 Hz).

[2044] Elementary Analysis: for C₁₈H₁₇N₅

[2045] Calcd.: C, 71.27; H, 5.65; N, 23.09.

[2046] Found: C, 70.87; H, 5.57; N, 22.78.

EXAMPLE 2-133

[2047]4-Chloro-3,8-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2048] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazino-3-methylpyridine (57% yield).

[2049] mp: 182-185° C. (recrystallized from chloroform/methanol).

[2050] NMR (CDCl₃) δ: 2.42 (3H, s), 2.70 (3H, s), 2.99 (3H, s),7.32-7.50 (2H, m), 7.62 (1H, d, J=6.6 Hz), 7.77-7.85 (1H, m), 8.26 (1H,d, J=8.8 Hz), 8.54 (1H, dd, J=1.5 Hz, 4.4 Hz).

[2051] Elementary Analysis: for C₁₈H₁₅ClN₄

[2052] Calcd.: C, 66.98; H, 4.68; N, 17.36.

[2053] Found: C, 67.10; H, 4.61; N, 17.13.

EXAMPLE 2-134

[2054]3,8-Dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2055] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinolineand sodium azide (68% yield).

[2056] mp: 199-202° C. (recrystallized from ethyl acetate).

[2057] NMR (CDCl₃) δ: 2.43 (3H, s), 2.61 (3H, s), 2.76 (3H, s), 5.51(2H, br s), 7.16 (1H, t, J=7.7 Hz), 7.30 (1H, dd, J=4.8 Hz, 7.7 Hz),7.48 (1H, d, J=6.6 Hz), 7.67 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=7.7 Hz),8.52 (1H, dd, J=1.5 Hz, 4.8 Hz).

[2058] Elementary Analysis: for C₁₈H₁₇N₅

[2059] Calcd.: C, 71.27; H, 5.65; N, 23.09.

[2060] Found: C, 71.23; H, 5.60; N, 22.87.

EXAMPLE 2-135

[2061]3,8-Dimethyl-1-(3-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2062] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(3-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(72% yield).

[2063] mp: 193-195° C. (recrystallized from ethanol).

[2064] NMR (CDCl₃) δ: 2.56 (3H, s), 2.73 (3H, s), 2.80 (3H, s), 4.23(1H, br s), 7.18 (1H, d, J=7.7 Hz), 7.23 (1H, t, J=8.1 Hz), 7.47-7.54(1H, m), 7.71-7.78 (1H, m), 8.32-8.41 (2H, m).

[2065] Elementary Analysis: for C₁₈H₁₆N₄O.HCl.0.7H₂O

[2066] Calcd.: C, 61.17; H, 5.25; N, 15.85.

[2067] Found: C, 61.22; H, 5.53; N, 15.76.

EXAMPLE 2-136

[2068] 4-Chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2069] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(3-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50%yield).

[2070] mp: 144-145° C. (recrystallized from ethyl acetate).

[2071] NMR (CDCl₃) δ: 2.93 (3H, s), 7.46 (1H, dd, J=4.8 Hz, 8.2 Hz),7.52-7.60 (1H, m), 7.76-7.84 (1H, m), 8.11 (1H, d, J=8.2 Hz), 8.33-8.38(1H, m), 8.53 (1H, dd, J=1.4 Hz, 4.8 Hz), 8.81 (1H, ddd, J=1.4 Hz, 2.6Hz, 8.4 Hz), 9.79-9.80 (1H, m).

[2072] Elementary Analysis: for C₁₆H₁₁ClN₄

[2073] Calcd.: C, 65.20; H, 3.76; N, 19.01; Cl, 12.03.

[2074] Found: C, 65.22; H, 3.73; N, 19.13; Cl, 11.91.

EXAMPLE 2-137

[2075] 3-Methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminedihydrochloride

[2076] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and sodiumazide (72% yield).

[2077] mp: 234-237° C. (recrystallized from methanol).

[2078] NMR (DMSO-d₆) δ: 2.83 (3H, s), 7.53 (1H, t, J=8.1 Hz), 7.83-8.05(3H, m), 8.58-8.85 (3H, m), 9.00 (2H, br s), 9.32 (1H, br s).

[2079] Elementary Analysis: for C₁₆H₁₃N₅.2HCl.2H₂O

[2080] Calcd.: C, 50.01; H, 4.98; N, 18.23; Cl, 18.45.

[2081] Found: C, 49.98; H, 5.05; N, 18.18; Cl, 18.27.

EXAMPLE 2-138

[2082]3-Methyl-1-(3-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2083] Following the procedure described in Example 2-31, the titlecompound was prepared from4-chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (37%yield).

[2084] mp: 282-283° C. (recrystallized from ethanol).

[2085] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.26-7.34 (1H, m), 7.66-7.72 (3H,m), 8.15 (1H, ddd, J=1.4 Hz, 2.6 Hz, 8.2 Hz), 8.22 (1H, d, J=8.2 Hz),8.73 (1H, dd, J=1.4 Hz, 4.6 Hz), 8.96 (1H, d, J=2.6 Hz), 11.93 (1H, brs).

[2086] Elementary Analysis: for C₁₆H₁₂N₄O.0.5H₂O

[2087] Calcd.: C, 67.36; H, 4.59; N, 19.64.

[2088] Found: C, 67.50; H, 4.83; N, 19.61.

EXAMPLE 2-139

[2089] 4-Methoxy-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2090] Following the procedure described in Example 2-19, the titlecompound was prepared from4-chloro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline andmethanol (83% yield).

[2091] mp: 126-128° C. (recrystallized from ethyl acetate/hexane).

[2092] NMR (CDCl₃) δ: 2.88 (3H, s), 4.28 (3H, s), 7.43-7.53 (2H, m),7.73-7.82 (1H, m), 8.13 (1H, d, J=8.4 Hz), 8.27 (1H, dd, J=1.2 Hz, 8.4Hz), 8.52 (1H, dd, J=1.4 Hz, 4.6 Hz), 8.87 (1H, ddd, J=1.4 Hz, 2.6 Hz,8.4 Hz), 9.82 (1H, d, J=2.6 Hz).

[2093] Elementary Analysis: for C₁₇H₁₄N₄O

[2094] Calcd.: C, 70.33; H, 4.86; N, 19.30.

[2095] Found: C, 70.11; H, 4.86; N, 19.12.

EXAMPLE 2-140

[2096] 4-Chloro-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2097] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (73%yield).

[2098] mp: 165-168° C. (recrystallized from ethyl acetate).

[2099] NMR (CDCl₃) δ: 2.91 (3H, s), 7.56-7.64 (1H, m), 7.79-7.88 (1H,m), 8.15 (1H, d, J=8.4 Hz), 8.36 (1H, dd, J=0.7 Hz, 8.8 Hz), 8.56 (2H,dd, J=1.5 Hz, 5.0 Hz), 8.71 (2H, dd, J=1.5 Hz, 4.8 Hz).

[2100] Elementary Analysis: for C₁₆H₁₁ClN₄

[2101] Calcd.: C, 65.20; H, 3.76; N, 19.01; Cl, 12.03.

[2102] Found: C, 65.25; H, 3.79; N, 18.98; Cl, 12.05.

EXAMPLE 2-141

[2103] 3-Methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminedihydrochloride

[2104] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and sodiumazide (36% yield).

[2105] mp: 259-266° C. (recrystallized from ethanol).

[2106] NMR (DMSO-d₆) δ: 2.82 (3H, s), 4.34 (2H, br s), 7.40-7.49 (1H,m), 7.73-7.90 (2H, m), 8.55 (1H, d, J=8.4 Hz), 8.86 (2H, d, J=7.2 Hz),9.04 (2H, d, J=6.6 Hz).

[2107] Elementary Analysis: for C₁₆H₁₃N₅.2HCl

[2108] Calcd.: C, 55.19; H, 4.34; N, 20.11; Cl, 20.36.

[2109] Found: C, 54.93; H, 4.39; N, 19.84; Cl, 20.01.

EXAMPLE 2-142

[2110]N,N-Dimethyl-N-[3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine

[2111] Following the procedure described in Example 2-8, the titlecompound was prepared from4-chloro-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and asolution of 2M dimethylamine in tetrahydrofuran (51% yield).

[2112] mp: 155-156° C. (recrystallized from ethyl acetate).

[2113] NMR (CDCl₃) δ: 2.82 (3H, s), 3.37 (6H, s), 7.37-7.46 (1H, m),7.68-7.76 (1H, m), 8.12 (1H, d, J=8.6 Hz), 8.18 (1H, d, J=8.8 Hz), 8.61(2H, dd, J=1.6 Hz, 5.0 Hz), 8.68 (2H, dd, J=1.4 Hz, 5.2 Hz).

[2114] Elementary Analysis: for C₁₈H₁₇N₅

[2115] Calcd.: C, 71.21; H, 5.65; N, 23.09.

[2116] Found: C, 71.24; H, 5.52; N, 23.12.

EXAMPLE 2-143

[2117]3-Methyl-1-(4-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2118] Following the procedure described in Example 2-12, the titlecompound was prepared from2-[[3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (61%yield).

[2119] mp: >300° C. (recrystallized from ethyl acetate/methanol).

[2120] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.32 (1H, ddd, J=1.6 Hz, 6.6 Hz,8.0 Hz), 7.65-7.78 (2H, m), 7.83 (2H, d, J=6.2 Hz), 8.21 (1H, dd, J=1.4Hz, 8.0 Hz), 8.79 (2H, d, J=6.2 Hz), 11.94 (1H, br s).

[2121] Elementary Analysis: for C₁₆H₁₂N₄O.0.5H₂O

[2122] Calcd.: C, 67.36; H, 4.59; N, 19.64.

[2123] Found: C, 67.62; H, 4.44; N, 19.69.

EXAMPLE 2-144

[2124] 4-Chloro-3-methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinoline

[2125] Following the methods described in Reference Example 2-3 andExample 2-1, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyrimidine (69%yield).

[2126] mp: 257-260° C. (recrystallized from ethyl acetate).

[2127] NMR (CDCl₃) δ: 2.80 (3H, s), 7.24-7.36 (2H, m), 7.54-7.73 (2H,m), 8.43-8.50 (1H, m), 8.89 (2H, dd, J=1.5 Hz, 5.1 Hz).

[2128] Elementary Analysis: for C₁₅H₁₀ClN₅

[2129] Calcd.: C, 60.92; H, 3.41; N, 23.68; Cl, 11.99.

[2130] Found: C, 60.63; H, 3.49; N, 23.59; Cl, 11.79.

EXAMPLE 2-145

[2131] 3-Methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[2132] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-3-methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (53% yield).

[2133] mp: 287-290° C. (recrystallized from methanol).

[2134] NMR (DMSO-d₆) δ: 2.84 (3H, s), 7.50-7.63 (2H, m), 7.87-7.98 (1H,m), 8.29 (1H, d, J=8.4 Hz), 8.73 (1H, d, J=8.1 Hz), 8.92 (2H, br s),9.00 (2H, d, J=4.8 Hz).

[2135] Elementary Analysis: for C₁₅H₁₂N₆.HCl.3H₂O

[2136] Calcd.: C, 49.12; H, 5.22; N, 22.91.

[2137] Found: C, 49.53; H, 4.94; N, 22.83.

EXAMPLE 2-146

[2138]3-Methyl-1-(2-pyrimidinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2139] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyrimidinyl)-1H-pyrazolo[3,4-b]quinoline (69%yield).

[2140] mp: 263-264° C. (recrystallized from ethanol).

[2141] NMR (DMSO-d₆) δ: 2.62 (3H, s), 7.32-7.41 (1H, m), 7.53 (1H, t,J=4.8 Hz), 7.70-7.79 (1H, m), 8.06 (1H, d, J=7.6 Hz), 8.24 (1H, dd,J=1.4 Hz, 8.2 Hz), 8.97 (2H, d, J=4.8 Hz), 11.88 (1H, br s).

[2142] Elementary Analysis: for C₁₅H₁₁N₅O.0.2H₂O

[2143] Calcd.: C, 64.14; H, 4.09; N, 24.93.

[2144] Found: C, 64.20; H, 4.29; N, 25.07.

EXAMPLE 2-147

[2145]4-Chloro-1-(4,6-dimethyl-2-pyrimidinyl)-3-methyl-1H-pyrazolo[3,4-b]quinoline

[2146] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazino-4,6-dimethylpyrimidine (67% yield).

[2147] mp: 191-192° C. (recrystallized from ethyl acetate).

[2148] NMR (CDCl₃) δ: 2.69 (6H, s), 3.01 (3H, s), 7.02 (1H, s), 7.61(1H, ddd, J=1.2 Hz, 8.4 Hz, 8.6 Hz), 7.83 (1H, ddd, J=1.6 Hz, 8.4 Hz,8.6 Hz), 8.24 (1H, d, J=8.4 Hz), 8.41 (1H, dd, J=1.2 Hz, 8.6 Hz).

[2149] Elementary Analysis: for C₁₇H₁₄ClN₅

[2150] Calcd.: C, 63.06; H, 4.36; N, 21.63; Cl, 10.95.

[2151] Found: C, 63.12; H, 4.29; N, 21.63; Cl, 10.91.

EXAMPLE 2-148

[2152]1-(4,6-Dimethyl-2-pyrimidinyl)-3-methyl-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2153] Following the procedure described in Example 2-12, the titlecompound was prepared from2-[[3-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-1H-pyrazol-5-yl]amino]benzoicacid (49% yield).

[2154] mp: 312-315° C. (recrystallized from ethanol).

[2155] NMR (DMSO-d₆) δ: 2.61 (9H, s), 7.26 (1H, s), 7.31-7.40 (1H, m),7.69-7.78 (1H, m), 7.92 (1H, d, J=8.0 Hz), 8.23 (1H, dd, J=1.2 Hz, 8.2Hz), 11.66 (1H, br s).

[2156] Elementary Analysis: for C₁₁H₁₅N₅O

[2157] Calcd.: C, 66.87; H, 4.95; N, 22.94.

[2158] Found: C, 66.80; H, 4.84; N, 22.95.

EXAMPLE 2-149

[2159]4-Chloro-3-methyl-1-(1,3-thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoline

[2160] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]amino]benzoic acid(68% yield).

[2161] mp: 208-209° C. (recrystallized from ethyl acetate/methanol).

[2162] NMR (CDCl₃) δ: 2.96 (3H, s), 7.19 (1H, d, J=3.4 Hz), 7.58-7.66(1H, m), 7.73 (1H, d, J=3.4 Hz), 7.81-7.89 (1H, m), 8.25 (1H, d, J=8.8Hz), 8.39 (1H, dd, J=1.4 Hz, 8.8 Hz).

[2163] Elementary Analysis: for C₁₄H₉ClN₄S

[2164] Calcd.: C, 55.91; H, 3.02; N, 18.63; Cl, 11.79; S, 10.66.

[2165] Found: C, 56.00; H, 2.93; N, 18.51; Cl, 11.66; S, 10.83.

EXAMPLE 2-150

[2166]3-Methyl-1-(1,3-thiazol-2-yl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2167] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3-methyl-1-(1,3-thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (48% yield).

[2168] mp: 261-263° C. (recrystallized from methanol).

[2169] NMR (DMSO-d₆) δ: 2.81 (3H, s), 7.31-7.40 (1H, m), 7.44 (1H, d,J=3.7 Hz), 7.58 (2H, br s), 7.61 (1H, d, J=3.7 Hz), 7.66-7.75 (1H, m),7.83 (1H, dd, J=1.1 Hz, 8.4 Hz), 8.46 (1H, dd, J=1.1 Hz, 8.4 Hz).

[2170] Elementary Analysis: for C₁₄H₁₁N₅S

[2171] Calcd.: C, 59.77; H, 3.94; N, 24.89.

[2172] Found: C, 59.42; H, 3.93; N, 24.53.

EXAMPLE 2-151

[2173]3-Methyl-1-(1,3-thiazol-2-yl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2174] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-1-(1,3-thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoline (61%yield).

[2175] mp: 226-227° C. (recrystallized from ethyl acetate).

[2176] NMR (DMSO-d₆) δ: 2.60 (3H, s), 7.35 (1H, t, J=7.6 Hz), 7.60 (1H,d, J=3.6 Hz), 7.67-7.76 (1H, m), 7.80 (1H, d, J=3.6 Hz), 8.12 (1H, d,J=8.4 Hz), 8.22 (1H, dd, J=1.0 Hz, 7.6 Hz), 11.72 (1H, br s).

[2177] Elementary Analysis: for C₁₄H₁₀N₄OS

[2178] Calcd.: C, 59.56; H, 3.57; N, 19.85; S, 11.36.

[2179] Found: C, 59.63; H, 3.53; N, 19.85; S, 11.36.

EXAMPLE 2-152

[2180]4-Chloro-3,8-dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinoline

[2181] Following the procedure described in Reference Example 2-3 andExample 2-1, the title compound was prepared from8-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and2-hydrazinoquinoline which was previously prepared form2-chloroquinoline following the method described in Reference Example2-2 (42% yield).

[2182] mp: 165-168° C. (recrystallized from methanol/chloroform).

[2183] NMR (CDCl₃) δ: 2.91 (3H, s), 3.04 (3H, s), 7.44-7.57 (2H, m),7.65-7.80 (2H, m), 8.10 (1H, br d, J=8.4 Hz), 8.22-8.30 (2H, m), 8.38(1H, d, J=8.8 Hz), 9.21 (1H, d, J=8.8 Hz).

EXAMPLE 2-153

[2184]3,8-Dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2185] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinoline andsodium azide (42% yield).

[2186] mp: 273-276° C. (recrystallized from ethyl acetate/methanol). NMR(CDCl₃) δ: 2.84 (3H, s), 2.93 (3H, s), 5.86 (2H, br s), 7.22-7.30 (1H,m), 7.48 (1H, t, J=7,0 Hz), 7.58 (1H, d, J=7.0 Hz), 7.70 (1H, t, J=1.5Hz, 7.0 Hz), 7.83 (2H, d, J=8.1 Hz), 8.23 (1H, d, J=8.1 Hz), 8.34 (1H,d, J=8.8 Hz), 9.46 (1H, d, J=8.8 Hz).

[2187] Elementary Analysis: for C₂₁H₁₇N₅

[2188] Calcd.: C, 74.32; H, 5.05; N, 20.63.

[2189] Found: C, 73.83; H, 4.98; N, 20.31.

EXAMPLE 2-154

[2190]3,8-Dimethyl-1-(2-quinolinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2191] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3,8-dimethyl-1-(2-quinolinyl)-1H-pyrazolo[3,4-b]quinoline (63%yield).

[2192] mp: 255-257° C. (recrystallized from ethanol).

[2193] NMR (DMSO-d₆) δ: 2.45 (3H, s), 2.51 (3H, s), 7.12 (1H, t, J=7.0Hz), 7.43-7.58 (2H, m), 7.66-8.00 (5H, m), 8.39 (1H, d, J=8.4 Hz).

[2194] Elementary Analysis: for C₂₁H₁₆N₄O

[2195] Calcd.: C, 74.10; H, 4.74; N, 16.46.

[2196] Found: C, 74.10; H, 4.76; N, 16.49.

EXAMPLE 2-155

[2197]4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]thieno[2,3-e]pyridine

[2198] Following the procedure described in Example 2-1, the titlecompound was prepared from3-[[3-methyl-1-(2-pyridinyl-1H-pyrazol-5-yl)amino]-2-thiphenecarboxylicacid (49% yield).

[2199] mp: 230-231° C. (recrystallized from ethyl acetate/acetonitrile).

[2200] NMR (CDCl₃) δ: 2.93 (3H, s), 7.22-7.27 (1H, m), 7.62 (1H, d,J=5.6 Hz), 7.88-7.97 (2H, m), 8.61 (1H, d, J=8.0 Hz), 8.69 (1H, d, J=4.4Hz).

[2201] Elementary Analysis: for C₁₄H₉ClN₄S

[2202] Calcd.: C, 55.91; H, 3.02; N, 18.63.

[2203] Found: C, 55.96; H, 3.12; N, 18.72.

EXAMPLE 2-156

[2204]3-Methyl-1-(2-pyridinyl)-1,8-dihydro-4H-pyrazolo[3,4-b]thieno[2,3-e]pyridin-4-one

[2205] Following the procedure described in Example 2-12, the titlecompound was prepared from3-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-thiphenecarboxylicacid (28% yield).

[2206] mp: 228-229° C. (recrystallized from ethyl acetate).

[2207] NMR (DMSO-d₆) δ: 2.61 (3H, s), 7.36-7.42 (1H, m), 7.63 (1H, d,J=5.2 Hz), 7.91 (1H, d, J=8.0 Hz), 8.02-8.10 (2H, m), 8.59-8.62 (1H, m),12.60 (1H, br s).

[2208] Elementary Analysis: for C₁₄H₁₀N₄OS.0.5H₂O

[2209] Calcd.: C, 57.72; H, 3.81; N, 19.23.

[2210] Found: C, 57.32; H, 3.88; N, 19.19.

EXAMPLE 2-157

[2211] 4-Chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2212] A solution of 2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (62.0 g, 0.221 mol) in phosphorous oxychloride (166 g, 1.08 mol)was heated under reflux for 1 hour. The solution was allowed to cool toroom temperature and poured into water. The solution was neutralized byaddition of a sodium hydroxide solution, and the organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (chloroform) to give thetitle compound (47.4 g, 76% yield).

[2213] mp: 153-156° C. (recrystallized from ethyl acetate/methanol).

[2214] NMR (CDCl₃) δ: 7.25-7.33 (1H, m), 7.58-7.67 (1H, m), 7.80-7.89(1H, m), 7.93-8.01 (1H, m), 8.23 (1H, m), 8.39 (1H, m), 8.59 (1H, s),8.70 (1H, br d, J=5.1 Hz), 8.78 (1H, d, J=8.4 Hz).

[2215] Elementary Analysis: for C₁₅H₉ClN₄

[2216] Calcd.: C, 64.18; H, 3.23; N, 19.96.

[2217] Found: C, 64.04; H, 3.01; N, 19.94.

EXAMPLE 2-158

[2218] 1-(2-Pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[2219] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and sodium azide(78% yield).

[2220] mp: 312-315° C. (recrystallized from methanol).

[2221] NMR (DMSO-d₆) δ: 7.47-7.55 (1H, m), 7.63 (1H, t, J=7.7 Hz),7.95-8.21 (3H, m), 8.45 (1H, d, J=8.4 Hz), 8.65-8.75 (2H, m), 9.11 (1H,s), 10.2 (2H, br s).

[2222] Elementary Analysis: for C₁₅H₁₁N₅.HCl

[2223] Calcd.: C, 60.51; H, 4.06; N, 23.52; Cl, 11.91.

[2224] Found: C, 60.61; H, 4.06; N, 23.30; Cl, 11.83.

EXAMPLE 2-159

[2225] 1-(2-Pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2226] A solution of methanesulfonic acid (20 mL, 0.31 mol) inphosphorus pentoxide (5.00 g, 35.2 mmol) was heated at 100° C. Themixture was stirred at the same temperature, while powdery2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (1.94 g, 6.92mmol) was added in small portions. The reaction mixture was heated andstirred at the same temperature for 10 minutes. The mixture was allowedto cool to room temperature, and iced water was added thereto. Thesolution was made basic by the addition of an aqueous sodium hydroxidesolution, and the organic matter was extracted with ethyl acetate. Theextract was washed with saturated brine and water, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (chloroform:methanol=99:1) to give the titlecompound (1.35 g, 74% yield).

[2227] mp: 240-242° C. (recrystallized from ethanol).

[2228] NMR (DMSO-d₆) δ: 7.32-7.40 (1H, m), 7.42-7.49 (1H, m), 7.71-7.80(1H, m), 7.96-8.01 (1H, m), 8.07-8.15 (2H, m), 8.24-8.29 (1H, m), 8.39(1H, s), 8.64-8.68 (1H, m), 12.03 (1H, br s).

[2229] Elementary Analysis: for C₁₅H₁₀N₄O

[2230] Calcd.: C, 68.69; H, 3.84; N, 21.36.

[2231] Found: C, 68.68; H, 3.89; N, 21.36.

EXAMPLE 2-160

[2232] 4,6-Dichloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2233] Following the procedure described in Example 2-1, the titlecompound was prepared from5-chloro-2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (25%yield).

[2234] mp: 175-176° C. (recrystallized from ethyl acetate).

[2235] NMR (CDCl₃) δ: 7.28-7.34 (1H, m), 7.77 (1H, dd, J=2.4 Hz, 9.0Hz), 7.93-8.01 (1H, m), 8.18 (1H, d, J=9.0 Hz), 8.37 (1H, d, J=2.4 Hz),8.59 (1H, s), 8.66-8.71 (2H, m).

[2236] Elementary Analysis: for C₁₅H₈Cl₂N₄.0.5H₂O

[2237] Calcd.: C, 55.58; H, 2.80; N, 17.28; Cl, 21.87.

[2238] Found: C, 55.42; H, 2.74; N, 17.25; Cl, 21.80.

EXAMPLE 2-161

[2239]6-Chloro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2240] Following the procedure described in Example 2-13, the titlecompound was prepared from4,6-dichloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (76% yield).

[2241] mp: 297-298° C. (recrystallized from ethanol).

[2242] NMR (DMSO-d₆) δ: 7.46 (1Hm, ddd, J=1.0 Hz, 5.0 Hz, 7.4 Hz), 7.79(1H, dd, J=2.6 Hz, 8.8 Hz), 7.97 (1H, d, J=8.0 Hz), 8.07-8.20 (3H, m),8.40 (1H, s), 8.63-8.66 (1H, m), 11.89 (1H, br s).

[2243] Elementary Analysis: for C₁₅H₉ClN₄O

[2244] Calcd.: C, 60.72; H, 3.06; N, 18.88; Cl, 11.95.

[2245] Found: C, 60.52; H, 3.04; N, 18.79; Cl, 11.89.

EXAMPLE 2-162

[2246] 4-Chloro-5-fluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2247] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from 2-fluoro-6-iodobenzoicacid and 1-(2-pyridinyl)-1H-pyrazol-5-ylamine (64% yield).

[2248] mp: 173-176° C. (recrystallized from ethyl acetate).

[2249] NMR (CDCl₃) δ: 7.18-7.34 (2H, m), 7.66-7.79 (1H, m), 7.92-8.07(2H, m), 8.62 (1H, s), 8.66-8.73 (2H, m).

[2250] Elementary Analysis: for C₁₅H₈ClFN₄

[2251] Calcd.: C, 60.31; H, 2.70; N, 18.76; Cl, 11.87; F, 6.36.

[2252] Found: C, 60.14; H, 2.57; N, 18.79; Cl, 11.81; F, 6.33.

EXAMPLE 2-163

[2253]5-Fluoro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2254] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-5-fluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (92%yield).

[2255] mp: 278-281° C. (recrystallized from ethanol).

[2256] NMR (DMSO-d₆) δ: 7.04 (1H, dq, J=1.0 Hz, 8.0 Hz), 7.46 (1H, dq,J=1.0 Hz, 4.8 Hz), 7.63-8.16 (4H, m), 8.34 (1H, s), 8.62-8.67 (1H, m),12.00 (1H, br s).

[2257] Elementary Analysis: for C₁₅H₉FN₄O.0.2H₂O

[2258] Calcd.: C, 63.47; H, 3.34; N, 19.74; F, 6.69.

[2259] Found: C, 63.25; H, 3.42; N, 19.79; F, 6.62.

EXAMPLE 2-164

[2260] 4-Chloro-6-fluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2261] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from 2-fluoro-5-iodobenzoicacid and 1-(2-pyridinyl)-1H-pyrazol-5-ylamine (40% yield).

[2262] mp: 176-179° C. (recrystallized from ethyl acetate/hexane).

[2263] NMR (CDCl₃) δ: 7.26-7.35 (1H, m), 7.59-7.70 (1H, m), 7.93-8.02(2H, m), 8.26.(1H, dd, J=5.4 Hz, 9.4 Hz), 8.59 (1H, s), 8.63-8.73 (2H,m).

[2264] Elementary Analysis: for C₁₅H₈ClFN₄.0.2H₂O

[2265] Calcd.: C, 59.60; H, 2.80; N, 18.53; Cl, 11.73; F, 6.28.

[2266] Found: C, 59.58; H, 2.79; N, 18.62; Cl, 11.56; F, 6.02.

EXAMPLE 2-165

[2267]6-Fluoro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2268] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-6-fluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (56%yield).

[2269] mp: 263-266° C. (recrystallized from ethanol/tetrahydrofuran).

[2270] NMR (DMSO-d₆) δ: 7.18-7.35 (2H, m), 7.61 (1H, dd, J=5.0 Hz, 9.0Hz), 7.81 (1H, dd, J=3.3 Hz, 10.2 Hz), 7.91-8.01 (1H, m), 8.11 (1H, s),8.47-8.51 (1H, m), 8.92 (1H, d, J=8.4 Hz), hidden (1H).

[2271] Elementary Analysis: for C₁₅H₉FN₄O.0.8HCl

[2272] Calcd.: C, 58.22; H, 3.19; N, 18.11; F, 6.14.

[2273] Found: C, 58.09; H, 2.90; N, 17.71; F, 5.84.

EXAMPLE 2-166

[2274]4-Chloro-1-(2-pyridinyl)-3-trifluoromethyl-1H-pyrazolo[3,4-b]quinoline

[2275] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from o-iodobenzoic acid and1-(2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-ylamine (53% yield).

[2276] mp: 166-168° C. (recrystallized from ethyl acetate/hexane).

[2277] NMR (CDCl₃) δ: 7.36-7.43 (1H, m), 7.65-7.74 (1H, m), 7.86-8.07(2H, m), 8.23 (1H, d, J=8.6 Hz), 8.48-8.54 (1H, m), 8.62 (1H, d, J=8.4Hz), 8.74-8.79 (1H, m).

[2278] Elementary Analysis: for C₁₆H₈ClF₃N₄

[2279] Calcd.: C, 55.11; H, 2.31; N, 16.07.

[2280] Found: C, 55.12; H, 2.19; N, 16.26.

EXAMPLE 2-167

[2281]1-(2-Pyridinyl)-3-trifluoromethyl-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2282] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-1-(2-pyridinyl)-3-trifluoromethyl-1H-pyrazolo[3,4-b]quinoline(78% yield).

[2283] mp: 231-233° C. (recrystallized from ethanol).

[2284] NMR (DMSO-d₆) δ: 7.36-7.44 (1H, m), 7.51-7.57 (1H, m), 7.76-7.83(1H, m), 7.99-8.28 (4H, m), 8.69-8.71 (1H, m), 12.19 (1H, br s).

[2285] Elementary Analysis: for C₁₆H₉F₃N₄O.0.25H₂O

[2286] Calcd.: C, 57.40; H, 2.86; N, 16.74; F, 17.03.

[2287] Found: C, 57.45; H, 2.84; N, 16.89; F, 16.96.

EXAMPLE 2-168

[2288]3-Bromomethyl-4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2289] A solution of4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.22 g,4.1 mmol), N-bromosuccinimide (0.87 g, 4.9 mmol) and2,2′-azobis(isobutyronitrile) (66 mg, 0.4 mmol) in carbon tetrachloride(40 mL) was heated under reflux under an argon atmosphere for 3 hours.The solution was allowed to cool to room temperature, the insolublesolid was removed and the solution was concentrated under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography (hexane:chloroform:ethyl acetate=2:1:1) to give the titlecompound (0.82 g, 53% yield).

[2290] mp: 203-205° C. (recrystallized from ethyl acetate/methanol).

[2291] NMR (CDCl₃) δ: 5.17 (2H, s), 7.26-7.34 (1H, m), 7.60-7.70 (1H,m), 7.82-8.03 (2H, m), 8.18-8.24 (1H, m), 8.43-8.49 (1H, m), 8.68-8.73(1H, m), 8.82-8.87 (1H, m).

[2292] Elementary Analysis: for C₁₆H₁₀BrClN₄

[2293] Calcd.: C, 51.43; H, 2.70; N, 15.00; Br, 21.39; Cl, 9.49.

[2294] Found: C, 51.40; H, 2.72; N, 15.13; Br, 21.29; Cl, 9.73.

EXAMPLE 2-169

[2295] 4-Chloro-3-ethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2296] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from2-(2-oxobutyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine (43%yield).

[2297] mp: 132-135° C. (recrystallized from ethyl acetate/hexane).

[2298] NMR (DMSO-d₆) δ: 1.57 (3H, t, J=7.3 Hz), 3.41 (2H, q, J=7.3 Hz),7.30-7.38 (1H, m), 7.59-7.70 (1H, m), 7.81-7.95 (1H, m), 8.02-8.15 (1H,m), 8.34 (1H, d, J=8.1 Hz), 8.40-8.47 (1H, m), 8.86-8.95 (2H, m).

EXAMPLE 2-170

[2299] 3-Ethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[2300] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-3-ethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline and sodiumazide (62% yield).

[2301] mp: 249-252° C. (recrystallized from methanol).

[2302] NMR (DMSO-d₆) δ: 1.40 (3H, t, J=7.3 Hz), 3.30 (2H, q, J=7.3 Hz),7.44-7.68 (2H, m), 7.92-8.20 (3H, m), 8.43 (1H, d, J=8.4 Hz), 8.65-8.72(1H, m), 8.84 (1H, d, J=8.4 Hz), hidden (2H).

[2303] Elementary Analysis: for C₁₇H₁₅N₅.HCl.2.2H₂O

[2304] Calcd.: C, 55.88; H, 5.63; N, 19.16; Cl, 9.70.

[2305] Found: C, 55.81; H, 5.48; N, 19.18; Cl, 9.70.

EXAMPLE 2-171

[2306]3-Ethyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2307] Following the procedures described in Reference Example 2-3 andExample 2-12, the title compound was prepared from2-(2-oxobutyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinopyridine (43%yield).

[2308] mp: 191-193° C. (recrystallized from ethyl acetate).

[2309] NMR (DMSO-d₆) δ: 1.46 (3H, t, J=7.3 Hz), 3.17 (2H, q, J=7.3 Hz),7.20-7.25 (1H, m), 7.33 (1H, t, J=8.1 Hz), 7.43 (1H, d, J=8.4 Hz),7.60-7.70 (1H, m), 7.85-7.94 (1H, m), 8.04 (1H, d, J=8.4 Hz), 8.40-8.48(2H, m), 11.48 (1H, br s).

EXAMPLE 2-172

[2310] 4-Chloro-3-isopropyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2311] Following the procedures described in Reference Examples 2-68 and2-3, and Example 2-1, the title compound was prepared from Meldrum'sacid, isobutyryl chloride and 2-hydrazinopyridine (5% yield).

[2312] mp: 146-148° C. (recrystallized from ethyl acetate/hexane).

[2313] NMR (CDCl₃) δ: 1.61 (6H, d, J=6.8 Hz), 3.94-4.08 (1H, m),7.21-7.25 (1H, m), 7.56-7.63 (1H, m), 7.77-7.86 (1H, m), 7.88-7.97 (1H,m), 8.20 (1H, d, J=8.4 Hz), 8.43 (1H, dd, J=1.2 Hz, 8.8 Hz), 8.60 (1H,d, J=8.4 Hz), 8.72 (1H, d, J=4.0 Hz).

[2314] Elementary Analysis: for C₁₈H₁₅ClN₄

[2315] Calcd.: C, 66.98; H, 4.68; N, 17.36; Cl, 10.98.

[2316] Found: C, 67.19; H, 4.64; N, 17.58; Cl, 10.92.

EXAMPLE 2-173

[2317]3-Isopropyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2318] Following the procedures described in Reference Examples 2-68 and2-3, and Example 2-12, the title compound was prepared from Meldrum'sacid, isobutyryl chloride and 2-hydrazinopyridine (16% yield).

[2319] mp: 143-144° C. (recrystallized from ethyl acetate/hexane).

[2320] NMR (CDCl₃) δ: 1.50 (6H, d, J=6.8 Hz), 3.63-3.76 (1H, m),7.18-7.24 (1H, m), 7.29-7.37 (1H, m), 7.44 (1H, d, J=8.0 Hz), 7.61-7.69(1H, m), 7.90 (1H, dt, J=1.2 Hz, 8.4 Hz), 8.07 (1H, dd, J=0.8 Hz, 8.4Hz), 8.47-8.50 (2H, m), 11.55 (1H, br s).

[2321] Elementary Analysis: for C₁₈H₁₆N₄O

[2322] Calcd.: C, 71.04; H, 5.30; N, 18.41.

[2323] Found: C, 70.99; H, 5.30; N, 18.49.

EXAMPLE 2-174

[2324]3-Isobutyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2325] Following the procedures described in Reference Examples 2-11 and2-3, and Example 2-12, the title compound was prepared from Meldrum'sacid, isovaleryl chloride and 2-hydrazinopyridine (16% yield).

[2326] mp: 167-169° C. (recrystallized from ethyl acetate/hexane).

[2327] NMR (DMSO-d₆) δ: 0.99 (6H, d, J=6.6 Hz), 2.24-2.37 (1H, m), 2.91(2H, d, J=7.0 Hz), 7.32-7.45 (2H, m), 7.69-7.78 (1H, m), 7.94 (1H, d,J=8.0 Hz), 8.04-8.12 (2H, m), 8.24 (1H, dd, J=1.4 Hz, 8.0 Hz), 8.63-8.67(1H, m), 11.95 (1H, br s).

[2328] Elementary Analysis: for C₁₉H₁₈N₄O.0.2H₂O

[2329] Calcd.: C, 70.88; H, 5.76; N, 17.40.

[2330] Found: C, 70.93; H, 5.62; N, 17.45.

EXAMPLE 2-175

[2331] Methyl2-[4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-3-yl]acetate

[2332] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from o-iodobenzoic acid andmethyl 2-[5-amino-1-(2-pyridinyl)-1H-pyrazol-3-yl]acetate (24% yield).

[2333] mp: 152-153° C. (recrystallized from ethyl acetate/diethylether).

[2334] NMR (CDCl₃) δ: 3.75 (3H, s), 4.47 (2H, s), 7.24-7.31 (1H, m),7.58-7.82 (1H, m), 8.41-8.01 (2H, m), 8.21 (1H, d, J=8.6 Hz), 8.40 (1H,dd, J=1.2 Hz, 8.6 Hz), 8.67-8.72 (1H, m), 8.87 (1H, d, J=8.4 Hz).

[2335] Elementary Analysis: for C₁₈H₁₃ClN₄O₂

[2336] Calcd.: C, 61.28; H, 3.71; N, 15.88.

[2337] Found: C, 61.06; H, 3.78; N, 15.97.

EXAMPLE 2-176

[2338] Methyl2-[4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]acetate

[2339] Following the procedure described in Example 2-13, the titlecompound was prepared from methyl2-[4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-3-yl]acetate (84%yield).

[2340] mp: 240-241° C. (recrystallized from ethyl acetate).

[2341] NMR (CDCl₃) δ: 3.81 (3H, s), 4.21 (2H, s), 7.20-7.36 (2H, m),7.45 (1H, d, J=7.6 Hz), 7.65 (1H, ddd, J=1.6 Hz, 7.0 Hz, 8.4 Hz), 7.88(1H, ddd, J=1.6 Hz, 7.0 Hz, 8.4 Hz), 7.99 (1H, d, J=8.4 Hz), 8.41 (1H,d, J=8.0 Hz), 8.48-8.50 (1H, m), 11.41 (1H, s).

[2342] Elementary Analysis: for C₁₈H₁₄N₄O₃

[2343] Calcd.: C, 64.66; H, 4.22; N, 16.76.

[2344] Found: C, 64.56; H, 4.20; N, 16.88.

EXAMPLE 2-177

[2345]2-[4-Oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]aceticacid

[2346] To a solution of methyl2-[4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]acetate(5.47 g, 16.4 mmol) in methanol (150 mL), an aqueous 2N sodium hydroxidesolution (15 mL) was added at 0° C., and the mixture was stirred at roomtemperature for 2 hours, and refluxed further for 3 hours. The solutionwas allowed to cool to room temperature, made acidic by the addition ofan aqueous 2N hydrochloric acid solution, and the resulting precipitatewas collected by filtration. The collected crude crystals were washedwith water and dried to give the title compound (4.96 g, 95% yield).

[2347] mp: 229-231° C. (recrystallized from chloroform/methanol).

[2348] NMR (DMSO-d₆) δ: 4.02 (2H, s), 7.30-7.47 (2H, m), 7.68-7.80 (1H,m), 7.91 (1H, d, J=8.4 Hz), 8.02-8.25 (3H, m), 8.61-8.68 (1H, m), 11.99(1H, s), 12.6 (1H, br s).

[2349] Elementary Analysis: for C₁₇H₁₂N₄O₃.0.8H₂O

[2350] Calcd.: C, 61.00; H, 4.10; N, 16.74.

[2351] Found: C, 61.22; H, 4.09; N, 16.45.

EXAMPLE 2-178

[2352]2-[4-Oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]acetamide

[2353] To a solution of2-[4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]aceticacid (1.60 g, 5.0 mmol) in a mixed solvent of tetrahydrofuran (100 mL)and N,N-dimethylformamide (20 mL), 1,1′-carbonyldiimidazole (0.89 g, 5.5mmol) was added and the mixture was stirred at room temperature for 30minutes. Subsequently, 25% aqueous ammonia solution was added to themixture and the resulting solution was stirred at room temperature for 1hour. The solution was poured into water, and the resulting precipitatewas collected by filtration. The collected crude crystals were washedwith water, and dried to give the title compound (0.94 g, 59% yield).

[2354] mp: 302-305° C.

[2355] NMR (DMSO-d₆) δ: 3.87 (2H, s), 7.02 (1H, br s), 7.30-7.45 (2H,m), 7.70-7.79 (1H, m), 7.94 (1H, d, J=8.4 Hz), 8.03-8.13 (2H, m), 8.24(1H, dd, J=1.0 Hz, 8.0 Hz), 8.62-8.65 (1H, m) , 11.60 (2H, br s).

[2356] Elementary Analysis: for C₁₇H₁₃N₅O₂.0.2H₂O

[2357] Calcd.: C, 63.23; H, 4.18; N, 21.69.

[2358] Found: C, 63.27; H, 4.09; N, 21.44.

EXAMPLE 2-179

[2359] Ethyl4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline-3-carboxylate

[2360] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from o-iodobenzoic acid andethyl 5-amino-1-(2-pyridinyl)-1H-pyrazole-3-carboxylate (52% yield).

[2361] mp: 164-166° C. (recrystallized from ethyl acetate).

[2362] NMR (CDCl₃) δ: 1.53 (3H, t, J=7.4 Hz), 4.60 (2H, q, J=7.4 Hz),7.37 (1H, dq, J=1.0 Hz, 5.0 Hz), 7.62-7.72 (1H, m), 7.84-8.05 (2H, m),8.17-8.25 (1H, m), 8.50-8.80 (3H, m).

[2363] Elementary Analysis: for C₁₈H₁₃ClN₄O₂

[2364] Calcd.: C, 61.28; H, 3.71; N, 15.88; Cl, 10.05.

[2365] Found: C, 61.27; H, 3.80; N, 16.01; Cl, 9.82.

EXAMPLE 2-180

[2366] Ethyl4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylate

[2367] Following the procedures described in Reference Example 2-5 andExample 2-12, the title compound was prepared from o-iodobenzoic acidand ethyl 5-amino-1-(2-pyridinyl)-1H-pyrazole-3-carboxylate (63% yield).

[2368] mp: 183-186° C. (recrystallized from ethyl acetate).

[2369] NMR (CDCl₃) δ: 1.53 (3H, t, J=7.0 Hz), 4.59 (2H, q, J=7.0 Hz),7.25-7.48 (3H, m), 7.63-7.72 (1H, m), 7.91-8.01 (1H, m), 8.19 (1H, d,J=8.4 Hz), 8.48-8.60 (2H, m), 11.62 (1H, br s).

[2370] Elementary Analysis: for C₁₈H₁₄N₄O₃

[2371] Calcd.: C, 64.66; H, 4.22; N, 16.76.

[2372] Found: C, 64.63; H, 4.16; N, 16.76.

EXAMPLE 2-181

[2373]4-Oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylicacid

[2374] Following the procedure described in Example 2-177, the titlecompound was prepared from methyl4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylate(92% yield).

[2375] mp: 306-309° C.

[2376] NMR (DMSO-d₆) δ: 7.48-7.59 (2H, m), 7.92 (1H, ddd, J=1.4 Hz, 7.0Hz, 8.4 Hz), 8.03-8.07 (1H, m), 8.18 (1H, dd, J=1.8 Hz, 8.4 Hz),8.26-8.38 (2H, m), 8.71 (1H, d, J=4.4 Hz), 12.40 (1H, br s), hidden(1H).

[2377] Elementary Analysis: for C₁₆H₁₀N₄O₃

[2378] Calcd.: C, 62.74; H, 3.29; N, 18.29.

[2379] Found: C, 62.36; H, 3.21; N, 18.07.

EXAMPLE 2-182

[2380]3-Phenyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2381] Following the procedures described in Reference Example 2-5 andExample 2-12, the title compound was prepared from o-iodobenzoic acidand 3-phenyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine which was previouslyprepared from benzoylacetonitrile and 2-hydrazinopyridine following themethod described in Reference Example 2-72 (58% yield).

[2382] mp: 237-240° C. (recrystallized from ethyl acetate).

[2383] NMR (DMSO-d₆) δ: 7.34-7.57 (5H, m), 7.73-7.81 (1H, m), 7.81-8.15(3H, m), 8.31 (1H, dd, J=1.4 Hz, 8.2 Hz), 8.46-8.50 (2H, m), 8.67-8.70(1H, m), 12.21 (1H, br s).

[2384] Elementary Analysis: for C₂₁H₁₄N₄O

[2385] Calcd.: C, 74.54; H, 4.17; N, 16.56.

[2386] Found: C, 74.59; H, 4.20; N, 16.56.

EXAMPLE 2-183

[2387]4-Chloro-3-(4-methoxyphenyl)-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2388] Following the procedures described in Reference Example 2-5 andExample 2-1, the title compound was prepared from o-iodobenzoic acid and3-(4-methoxyphenyl)-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (86% yield).

[2389] mp: 205-207° C. (recrystallized from chloroform/methanol).

[2390] NMR (CDCl₃) δ: 3.92 (3H, s), 7.06 (2H, d, J=8.8 Hz), 7.25-7.35(1H, m), 7.56-7.67 (1H, m), 7.81 (2H, d, J=8.8 Hz), 7.85-8.03 (2H, m),8.24 (1H, d, J=8.8 Hz), 8.44 (1H, d, J=8.4 Hz), 8.70-8.80 (2H, m).

[2391] Elementary Analysis: for C₁₂H₁₅ClN₄O.H₂O

[2392] Calcd.: C, 65.27; H, 4.23; N, 13.84.

[2393] Found: C, 65.13; H, 4.48; N, 13.66.

EXAMPLE 2-184

[2394]3-(4-Methoxyphenyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinolin-4-ylaminehydrochloride

[2395] Following the procedures described in Examples 2-2 and 2-3, thetitle compound was prepared from4-chloro-3-(4-methoxyphenyl)-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(37% yield).

[2396] mp: 248-251° C. (recrystallized from ethanol).

[2397] NMR (DMSO-d₆) δ: 3.90 (3H, s), 7.22 (2H, d, J=8.8 Hz), 7.48-7.70(2H, m), 7.77 (2H, d, J=8.8 Hz), 7.99-8.20 (3H, m), 8.49 (1H, d, J=8.8Hz), 8.70-8.75 (1H, m), 8.79 (1H, d, J=8.4 Hz), 10.20 (2H, br s).

[2398] Elementary Analysis: for C₂₂H₁₇N₅O.HCl.3H₂O

[2399] Calcd.: C, 57.70; H, 5.28; N, 15.29; Cl, 7.74.

[2400] Found: C, 57.45; H, 5.20; N, 14.99; Cl, 8.05.

EXAMPLE 2-185

[2401]3-(4-Methoxyphenyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2402] Following the procedures described in Reference Example 2-5 andExample 2-12, the title compound was prepared from o-iodobenzoic acidand 3-(4-methoxyphenyl)-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (73%yield).

[2403] mp: 197-199° C. (recrystallized from ethyl acetate).

[2404] NMR (DMSO-d₆) δ: 3.86 (3H, s), 7.08 (2H, td, J=2.4 Hz, 9.0 Hz),7.37 (1H, t, J=7.5 Hz), 7.42-7.49 (1H, m), 7.72-7.80 (1H, m), 8.05-8.13(3H, m), 8.31 (1H, dd, J=1.2 Hz, 8.4 Hz), 8.50 (2H, td, J=2.4 Hz, 9.0Hz), 8.67 (1H, d, J=3.0 Hz), 12.20 (1H, br s).

[2405] Elementary Analysis: for C₂₂H₁₆N₄O₂

[2406] Calcd.: C, 71.73; H, 4.38; N, 15.21.

[2407] Found: C, 71.39; H, 4.35; N, 15.10.

EXAMPLE 2-186

[2408]4-Chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline

[2409] Following the procedures described in Reference Example 2-3 andExample 2-1, the title compound was prepared from2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one and 2-hydrazinomethylpyridinewhich was previously prepared from 2-chloromethylpyridine following themethod described in Reference Example 2-2 (75% yield).

[2410] mp: 113-115° C. (recrystallized from ethyl acetate).

[2411] NMR (CDCl₃) δ: 2.89 (3H, s), 5.88 (2H, s), 6.44 (1H, d, J=7.7Hz), 7.12-7.20 (1H, m), 7.46-7.62 (2H, m), 7.70-7.80 (1H, m), 8.06 (1H,d, J=8.8 Hz), 8.33-8.40 (1H, m), 8.55-8.61 (1H, m).

[2412] Elementary Analysis: for C₁₇H₁₃ClN₄

[2413] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[2414] Found: C, 66.27; H, 4.12; N, 18.11; Cl, 11.42.

EXAMPLE 2-187

[2415]3-Methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-ylamine

[2416] Following the procedure described in Example 2-2, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline (81%yield).

[2417] mp: 262-265° C. (recrystallized from ethanol).

[2418] NMR (DMSO-d₆) δ: 2.71 (3H, s), 6.00 (2H, s), 7.52-7.70 (3H, m),7.95-8.01 (2H, m), 8.10-8.20 (1H, m), 8.65-8.73 (2H, m), hidden (1H).

[2419] Elementary Analysis: for C₁₇H₁₅N₅.2HCl.0.5H₂O

[2420] Calcd.: C, 55.00; H, 4.89; N, 18.86; Cl, 19.10.

[2421] Found: C, 55.21; H, 4.89; N, 18.82; Cl, 19.21.

EXAMPLE 2-188

[2422]N,N-Dimethyl-N-[3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-yl]amine

[2423] Following the procedure described in Example 2-8, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline anda solution of 2M dimethylamine in tetrahydrofuran (81% yield).

[2424] mp: 166-168° C. (recrystallized from ethyl acetate).

[2425] NMR (CDCl₃) δ: 2.78 (3H, s), 3.37 (6H, s), 5.86 (2H, s), 6.98(1H, d, J=8.1 Hz), 7.10-7.19 (1H, m), 7.25-7.37 (1H, m), 7.49-7.68 (2H,m), 7.98 (1H, dd, J=0.73 Hz, 8.8 Hz), 8.17 (1H, dd, J=0.73 Hz, 8.8 Hz),8.58 (1H, br d, J=4.8 Hz).

[2426] Elementary Analysis: for C₁₉H₁₉N₅

[2427] Calcd.: C, 71.90; H, 6.03; N, 22.07.

[2428] Found: C, 71.72; H, 6.03; N, 21.90.

EXAMPLE 2-189

[2429]3-Methyl-1-(2-pyridinylmethyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2430] Following the procedure described in Example 2-19, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline andmethanol (23% yield).

[2431] mp: 269-272° C. (recrystallized from ethyl acetate/methanol).

[2432] NMR (DMSO-d₆) δ: 2.51 (3H, s), 5.57 (2H, s), 7.14 (1H, d, J=8.1Hz), 7.25-7.38 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.65-7.85 (2H, m) , 8.23(1H, d, J=8.1 Hz) , 8.52 (1H, d, J=4.8 Hz).

[2433] Elementary Analysis: for C₁₇H₁₄N₄O

[2434] Calcd.: C, 70.33; H, 4.86; N, 19.30.

[2435] Found: C, 70.14; H, 4.80; N, 19.17.

EXAMPLE 2-190

[2436]4-Methoxy-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline

[2437] Following the procedure described in Example 2-19, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinoline andmethanol (70% yield).

[2438] mp: 111-113° C. (recrystallized from ethyl acetate/hexane).

[2439] NMR (CDCl₃) δ: 2.82 (3H, s), 4.26 (3H, s), 5.88 (2H, s), 7.01(1H, d, J=8.1 Hz), 7.10-7.20 (1H, m), 7.35-7.77 (3H, m), 8.04 (1H, d,J=8.1 Hz), 8.25 (1H, d, J=8.4 Hz), 8.59 (1H, d, J=5.8 Hz).

[2440] Elementary Analysis: for C₁₈H₁₆N₄O

[2441] Calcd.: C, 71.04; H, 5.30; N, 18.41.

[2442] Found: C, 70.97; H, 5.20; N, 18.29.

EXAMPLE 2-191

[2443]3-Methyl-1-(3-pyridinylmethyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2444] Following the procedure described in Example 2-12, the titlecompound was prepared from2-[[3-methyl-1-(3-pyridinylmethyl)-1H-pyrazol-5-yl]amino]benzoic acid(58% yield).

[2445] mp: 285-288° C. (recrystallized from ethyl acetate/methanol).

[2446] NMR (DMSO-d₆) δ: 2.50 (3H, s), 5.53 (2H, s), 7.21-7.73 (5H, m),8.19 (1H, d, J=8.1 Hz), 8.51 (1H, d, J=4.0 Hz), 8.55 (1H, s), 11.99 (1H,br s).

[2447] Elementary Analysis: for C₁₇H₁₄N₄O.0.1H₂O

[2448] Calcd.: C, 69.90; H, 4.90; N, 19.18.

[2449] Found: C, 69.64; H, 5.01; N, 18.95.

EXAMPLE 2-192

[2450]3-Methyl-1-(4-pyridinylmethyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2451] Following the procedure described in Example 2-12, the titlecompound was prepared from2-[[3-methyl-1-(4-pyridinylmethyl)-1H-pyrazol-5-yl]amino]benzoic acid(85% yield).

[2452] mp: 277-280° C. (recrystallized from ethyl acetate/methanol).

[2453] NMR (DMSO-d₆) δ: 2.52 (3H, s), 5.54 (2H, s), 7.13 (2H, d, J=6.0Hz), 7.21-7.33 (1H, m), 7.50 (1H, d, J=8.4 Hz), 7.60-7.72 (1H, m), 8.20(1H, dd, J=1.1 Hz, 8.4 Hz), 8.53 (2H, d, J=6.0 Hz), 11.96 (1H, br s).

[2454] Elementary Analysis: for C₁₇H₁₄N₄O

[2455] Calcd.: C, 70.33; H, 4.86; N, 19.30.

[2456] Found: C, 70.26; H, 4.84; N, 19.18.

EXAMPLE 2-193

[2457]3-Methyl-1-(2-pyridinyl)-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[4,3-b]pyridin-4(1H)-one

[2458] Following the procedure described below in Example 2-194, thetitle compound was prepared from ethyl 2-oxocyclopentanecarboxylate and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (17% yield).

[2459] mp: 218-219° C. (recrystallized from ethyl acetate).

[2460] NMR (CDCl₃) δ: 2.10-2.25 (2H, m), 2.69 (3H, s), 2.85 (2H, t,J=7.4 Hz), 3.01 (2H, t, J=7.2 Hz), 7.14-7.20 (1H, m), 7.81-7.90 (1H, m),7.96 (1H, d, J=8.0 Hz), 8.40 (1H, d, J=4.4 Hz), 11.23 (1H, br s).

[2461] Elementary Analysis: for C₁₅H₁₄N₄O.0.1H₂O

[2462] Calcd.: C, 67.20; H, 5.34; N, 20.90.

[2463] Found: C, 67.00; H, 5.12; N, 20.77.

EXAMPLE 2-194

[2464]3-Methyl-1-(2-pyridinyl)-1,5,6,7,8,9-hexahydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2465] A mixture of polyphosphoric acid (4.02 g) and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (1.75 g, 10.0 mmol) washeated at 130° C. The mixture was stirred at the same temperature, whileethyl 2-cyclohexanone carboxylate(1.70 mL, 10.6 mmol) was added theretogradually. The mixture was stirred at the same temperature further for 4hours. The solution was allowed to cool to room temperature, and waterwas added to the mixture. The solution was neutralized by the additionof a sodium hydroxide solution and the organic matter was extracted withchloroform. The extract was washed with saturated brine and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography (chloroform:methanol=100:1 to 50:1 to 20:1), andrecrystallized from ethyl acetate to give the title compound (0.39 g,14% yield).

[2466] mp: 172-173° C. (recrystallized from ethyl acetate).

[2467] NMR (CDCl₃) δ: 1.76-2.05 (4H, m), 2.60 (2H, t, J=5.4 Hz), 2.70(3H, s), 2.73 (2H, t, J=5.6 Hz), 7.13-7.20 (1H, m), 7.81-7.90 (1H, m),7.96 (1H, d, J=8.0 Hz), 8.40 (1H, dd, J=0.8 Hz, 5.2 Hz), 10.85 (1H, brs).

[2468] Elementary Analysis: for C₁₆H₁₆N₄O.0.75H₂O

[2469] Calcd.: C, 65.40; H, 6.00; N, 19.07.

[2470] Found: C, 65.50; H, 6.03; N, 19.08.

EXAMPLE 2-195

[2471]3-Methyl-1-(2-pyridinyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-4(1H)-one

[2472] Following the procedure described in Example 2-194, the titlecompound was prepared from methyl 2-oxo-1-cycloheptanecarboxylate and3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (15% yield).

[2473] mp: 184-185° C. (recrystallized from ethyl acetate-hexane).

[2474] NMR (CDCl₃) δ: 1.53-1.64 (2H, m), 1.77-1.88 (4H, m), 2.71 (3H,s), 2.85-2.90 (4H, m), 7.14-7.21 (1H, m), 7.82-7.90 (1H, m), 7.96 (1H,d, J=8.4 Hz), 8.41 (1H, dd, J=1.0 Hz, 5.3 Hz), 10.97 (1H, br s).

[2475] Elementary Analysis: for C₁₇H₁₈N₄O.H₂O

[2476] Calcd.: C, 65.37; H, 6.45; N, 17.94.

[2477] Found: C, 65.38; H, 6.30; N, 18.11.

EXAMPLE 2-196

[2478] 4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b][1,8]naphthyridine

[2479] Following the procedure described in Example 2-1, the titlecompound was prepared from2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]nicotinic acid (69%yield).

[2480] mp: 204-205° C. (recrystallized from ethyl acetate/methanol).

[2481] NMR (CDCl₃) δ: 3.03 (3H, s), 7.28 (1H, ddd, J=1.0 Hz, 5.0 Hz, 7.4Hz), 7.60 (1H, ddd, J=2.0 Hz, 4.2 Hz, 8.6 Hz), 7.97 (1H, ddd, J=1.8 Hz,7.4 Hz, 8.4 Hz), 8.69 (1H, ddd, J=0.8 Hz, 1.8 Hz, 5.0 Hz), 8.83 (1H, dd,J=2.0 Hz, 8.6 Hz), 9.01 (1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz), 9.26 (1H,dd, J=2.0 Hz, 4.2 Hz).

[2482] Elementary Analysis: for C₁₅H₁₀ClN₅.0.25H₂O

[2483] Calcd.: C, 60.01; H, 3.53; N, 23.33; Cl, 11.81.

[2484] Found: C, 60.30; H, 3.68; N, 23.11; Cl, 11.83.

EXAMPLE 2-197

[2485]3-Methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b][1,8]naphthylizin-4-one

[2486] Following the procedure described in Example 2-13, the titlecompound was prepared from4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b][1,8]naphthyridine(50% yield).

[2487] mp: >300° C. (recrystallized from chloroform/methanol).

[2488] NMR (DMSO-d₆) δ: 2.59 (3H, s), 7.14 (1H, dd, J=4.4 Hz, 7.8 Hz),7.22-7.28 (1H, m), 7.92-8.01 (1H, m), 8.48-8.65 (4H, m) , 11.89 (1H, brs).

[2489] Elementary Analysis: for C₁₅H₁₁N₅O.0.5HCl

[2490] Calcd.: C, 60.97; H, 3.92; N, 23.70.

[2491] Found: C, 61.14; H, 3.52; N, 23.70.

Reference Example 2-76

[2492] 4,5-Difluoro-2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid

[2493] A solution of 1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.94 g, 43.3mmol), 2-chloro-4,5-difluorobenzoic acid (10.0 g, 51.9 mmol), copperacetate (II) (0.787 g, 4.33 mmol) and potassium carbonate (5.98 g, 43.3mmol) in N,N-dimethylformamide (40 mL) was heated under reflux under anargon atmosphere for 3 hours. The solution was allowed to cool to roomtemperature, and poured into water. The solution was made weakly acidicby the addition of 6N hydrochloric acid, and the resulting crudecrystals were collected by filtration. The crystals were washed withwater and air dried to give the title compound (8.99 g, 55% yield).

[2494] mp: 242-245° C. (recrystallized from ethanol).

[2495] NMR (DMSO-d₆) δ: 6.51 (1H, d, J=2.0 Hz), 7.38 (1H, ddd, J=1.0 Hz,4.8 Hz, 7.2 Hz), 7.51 (1H, dd, J=7.0 Hz, 13.6 Hz), 7.72 (1H, d, J=2.0Hz), 7.84-7.95 (2H, m), 8.04 (1H, ddd, J=1.8 Hz, 7.2 Hz, 8.4 Hz), 8.47(1H, ddd, J=0.8 Hz, 1.8 Hz, 4.8 Hz), 12.24 (1H, br s), hidden (1H).

[2496] Elementary Analysis: for C₁₅H₁₀F₂N₄O₂.0.2H₂O

[2497] Calcd.: C, 56.32; H, 3.28; N, 17.52.

[2498] Found: C, 56.32; H, 3.18; N, 17.53.

Reference Example 2-77

[2499] 3-Oxopentanenitrile

[2500] A solution of ethyl cyanoacetate (17.0 g, 150 mmol), magnesiumchloride (14.4 g, 151 mmol) and triethylamine (42 mL, 301 mmol) inacetonitrile (150 mL) was stirred at 0° C. for 15 minutes. To thesolution, propionyl chloride (13.8 g, 150 mmol) was added dropwise over15 minutes at the same temperature, and subsequently the solution wasallowed to warm to room temperature and stirred for 24 hours. Afteraddition of 30% hydrochloric acid (100 mL), the organic matter wasextracted with diethylether. The extract was washed with saturated brineand dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give crude ethyl2-cyano-3-oxopentanoate (24.6 g, 97% yield). The compound (25.4 g, 150mmol) was dissolved in a mixed solvent of dimethylsulfoxide (50 mL) andwater (5 mL), and the solution was stirred at 120° C. for 1.5 hours. Thesolution was allowed to cool to room temperature and poured intosaturated brine, and the organic matter was extracted withdichloromethane. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvents were evaporated underreduced pressure to give the title compound (14.6 g, quantitative).

[2501] NMR (CDCl₃) δ: 1.14 (3H, t, J=7.4 Hz), 2.66 (2H, q, J=7.4 Hz),3.48 (2H, s).

Reference Example 2-78

[2502] 3-Ethyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine

[2503] To an ice-cold solution of 3-oxopentanenitrile (14.6 g, 150 mmol)and 2-hydrazinopyridine (13.6 g, 125 mmol) in ethanol (150 mL), aceticacid (14.3 mL, 250 mmol) was added and the resulting mixture was heatedunder reflux for 5 hours. The solution was allowed to cool to roomtemperature, and concentrated under reduced pressure, and water wasadded to the residue. The solution was made basic by the addition of anaqueous sodium hydroxide solution, and the organic matter was extractedwith ethyl acetate. The extract was washed with saturated brine andwater, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give the title compound (21.1 g, 90% yield).

[2504] NMR (CDCl₃) δ: 1.25 (3H, t, J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz),5.38 (1H, s), 5.90 (2H, br s), 7.04 (1H, ddd, J=1.2 Hz, 5.0 Hz, 7.4 Hz),7.75 (1H, ddd, J=2.0 Hz, 7.4 Hz, 8.4 Hz), 7.94 (1H, ddd, J=0.8 Hz, 1.2Hz, 8.4 Hz), 8.29 (1H, ddd, J=0.8 Hz, 2.0 Hz, 5.0 Hz).

Reference Example 2-79

[2505] 3-Methyl-1-(3-pyridinyl)-1H-pyrazol-5-ylamine dihydrochloride

[2506] A solution of aminocrotononitrile (8.21 g, 100 mmol) and3-hydrazinopyridine dihydrochloride (20.7 g, 114 mmol) in water (50 mL)was mixed with conc. hydrochloric acid (15 mL), and the mixture washeated under reflux for 30 minutes. The solution was allowed to cool toroom temperature, and the reaction solvent was evaporated under reducedpressure, and the resulting crystals were collected by filtration. Thecrystals obtained were washed with water and air dried to give the titlecompound (13.6 g, 55% yield).

[2507] NMR (DMSO-d₆) δ: 2.20 (3H, s), 5.61 (1H, s), 7.88 (1H, dd, J=5.0Hz, 8.4 Hz), 8.41 (1H, ddd, J=1.2 Hz, 2.4 Hz, 8.4 Hz), 8.75 (1H, dd,J=1.2 Hz, 5.0 Hz), 9.00 (1H, d, J=2.4 Hz), hidden (3H).

Reference Example 2-80

[2508] 3-Methyl-1-(4-pyridinyl)-1H-pyrazol-5-ylamine

[2509] A mixture of 4-chloropyridine hydrochloride (25.3 g, 169 mmol)and hydrazine monohydrate (40.0 mL, 825 mmol) was heated under refluxfor 1 hour. The solution was cooled to 0° C., and the resulting crystalswere collected by filtration. The crystals were washed with cold1-propanol and air dried to give crude 4-hydrazinopyridine (16.1 g, 88%yield). To a solution of the compound (7.64 g, 70.0 mmol) andaminocrotononitrile (5.75 g, 70.0 mmol) in water (30 mL), conc.hydrochloric acid (8 mL) was added and the mixture was heated underreflux for 30 minutes. The solution was allowed to cool to roomtemperature, made basic by the addition of an aqueous sodium hydroxidesolution, and the organic matter was extracted with chloroform. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(ethyl acetate to 10% methanol/ethyl acetate) to give the title compound(6.20 g, 51% yield)

[2510] mp: 109-110° C. (recrystallized from ethyl acetate/hexane).

[2511] NMR (CDCl₃) δ: 2.23 (3H, s), 3.92 (2H, br s), 5.51 (1H, s), 7.64(2H, dd, J=1.4 Hz, 4.8 Hz), 8.63 (2H, dd, J=1.4 Hz, 4.8 Hz).

[2512] Elementary Analysis: for C₉H₁₀N₄

[2513] Calcd.: C, 62.05; H, 5.79; N, 32.16.

[2514] Found: C, 62.12; H, 5.93; N, 32.10.

EXAMPLE 2-198

[2515] 4-Chloro-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2516] A solution of4,5-difluoro-2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(7.00 g, 22.1 mmol) in phosphorous oxychloride (10.3 mL, 111 mmol) washeated under reflux for 1 hour. The solution was allowed to cool to roomtemperature, and poured into iced water. After neutralization byaddition of a sodium hydroxide solution, the organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (chloroform) to give thetitle compound (3.99 g, 57% yield).

[2517] mp: 167-168° C. (recrystallized from ethyl acetate).

[2518] NMR (CDCl₃) δ: 7.32 (1H, ddd, J=1.0 Hz, 4.8 Hz, 7.4 Hz),7.93-8.03 (2H, m), 8.12 (1H, dd, J=8.6 Hz, 11.0 Hz), 8.57 (1H, s), 8.65(1H, ddd, J=0.8 Hz, 1.0 Hz, 8.4 Hz), 8.71 (1H, ddd, J=0.8 Hz, 1.8 Hz,4.8 Hz).

[2519] Elementary Analysis: for C₁₅H₇ClF₂N₄

[2520] Calcd.: C, 56.89; H, 2.23; N, 17.69; Cl, 11.19; F, 12.00.

[2521] Found: C, 57.00; H, 2.31; N, 17.79; Cl, 11.21; F, 12.02.

EXAMPLE 2-199

[2522]6,7-Difluoro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2523] To a solution of4-chloro-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (3.17g, 10.0 mmol) in ethanol (160 mL) was added 6 N hydrochloric acid (8 mL,48.0 mmol), and the mixture was heated under reflux for 6 hours. Thesolution was allowed to cool to room temperature, and the resultingcrystals were collected by filtration. The crystals were washed withethanol, air dried, and subsequently recrystallized from ethanol to givethe title compound (2.47 g, 83% yield).

[2524] mp: >300° C. (recrystallized from ethanol).

[2525] NMR (DMSO-d₆) δ: 7.42-7.49 (1H, m), 7.95 (1H, d, J=8.4 Hz),8.01-8.05 (2H, m), 8.22 (1H, dd, J=7.0 Hz, 12.4 Hz), 8.37 (1H, s),8.61-8.64 (1H, m), 12.15 (1H, br s).

[2526] Elementary Analysis: for C₁₅H₈F₂N₄O

[2527] Calcd.: C, 60.41; H, 2.70; N, 18.79; F, 12.74.

[2528] Found: C, 60.44; H, 2.73; N, 18.74; F, 12.84.

EXAMPLE 2-200

[2529]4-Chloro-3-ethyl-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2530] A solution of 3-ethyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (9.41g, 50.0 mmol), 2-chloro-4,5-difluorobenzoic acid (9.63 g, 50.0 mmol),copper acetate (II) (0.908 g, 5.00 mmol) and potassium carbonate (6.91g, 50.0 mmol) in N,N-dimethylformamide (50 mL) was heated under refluxunder an argon atmosphere for 2 hours. The solution was allowed to coolto room temperature, and poured into water. The solution was made weaklyacidic by the addition of 1N hydrochloric acid, and the resulting crudecrystals were collected by filtration. The crystals were washed withwater and air dried to give crude4,5-difluoro-2-[[3-ethyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (11.3 g, 66% yield). A solution of the compound (11.0 g, 31.9 mmol)in phosphorous oxychloride (15 mL, 161 mmol) was heated under reflux for2 hours. The solution was allowed to cool to room temperature, andpoured into iced water. The solution was neutralized by the addition ofa sodium hydroxide solution, and the organic matter was extracted withchloroform. The extract was washed with saturated brine and water, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (chloroform) to give the title compound (5.50g, 50% yield).

[2531] mp: 160-161° C. (recrystallized from ethyl acetate).

[2532] NMR (CDCl₃) δ: 1.53 (3H, t, J=7.5 Hz), 3.39 (2H, q, J=7.5 Hz),7.23-7.30 (1H, m), 7.87-7.98 (2H, m), 8.15 (1H, dd, J=8.4 Hz, 11.0 Hz),8.64-8.71 (2H, m).

[2533] Elementary Analysis: for C₁₇H₁₁ClF₂N₄

[2534] Calcd.: C, 59.23; H, 3.22; N, 16.25; Cl, 10.28; F, 11.02.

[2535] Found: C, 59.09; H, 3.12; N, 16.24; Cl, 10.25; F, 10.93.

EXAMPLE 2-201

[2536]3-Ethyl-6,7-difluoro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2537] To a solution of4-chloro-3-ethyl-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(2.49 g, 7.22 mmol) in ethanol (120 mL), 6N hydrochloric acid (6 mL,36.0 mmol) was added and the mixture was heated under reflux for 6hours. The solution was allowed to cool to room temperature, and theresulting crystals were collected by filtration. The crystals werewashed with ethanol, air dried, and recrystallized from ethanol to givethe title compound (1.73 g, 73% yield).

[2538] mp: 247-248° C. (recrystallized from ethanol).

[2539] NMR (DMSO-d₆) δ: 1.33 (3H, t, J=7.4 Hz), 2.98 (2H, q, J=7.4 Hz),7.41 (1H, ddd, J=1.0 Hz, 5.0 Hz, 7.4 Hz), 7.89 (1H, ddd, J=0.8 Hz, 1.0Hz, 8.4 Hz), 8.00 (1H, dd, J=9.0 Hz, 11.0 Hz), 8.07 (1H, ddd, J=1.8 Hz,7.4 Hz, 8.4 Hz), 8.18 (1H, dd, J=7.0 Hz, 12.0 Hz), 8.58 (1H, ddd, J=0.8Hz, 1.8 Hz, 5.0 Hz), 12.07 (1H, br s).

[2540] Elementary Analysis: for C₁₇H₁₂F₂N₄O

[2541] Calcd.: C, 62.57; H, 3.71; N, 17.17; F, 11.64.

[2542] Found: C, 62.40; H, 3.70; N, 17.12; F, 11.62.

EXAMPLE 2-202

[2543]4-Chloro-6,7-difluoro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2544] A solution of 3-methyl-1-(3-pyridinyl)-1H-pyrazol-5-ylaminedihydrochloride (11.0 g, 44.5 mmol), 2-chloro-4,5-difluorobenzoic acid(8.57 g, 44.5 mmol), copper acetate (II) (0.808 g, 4.45 mmol) andpotassium carbonate (12.3 g, 89.0 mmol) in N,N-dimethylformamide (50 mL)was heated under reflux under an argon atmosphere for 3 hours. Thesolution was allowed to cool to room temperature, and poured into water.The solution was made weakly acidic by the addition of 1N hydrochloricacid, and the resulting crude crystals were collected by filtration. Thecrystals were washed with water and air dried to give crude4,5-difluoro-2-[[3-methyl-1-(3-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (9.24 g, 63% yield). A solution of the compound (9.24 g, 28.0 mmol)in phosphorous oxychloride (13 mL, 139 mmol) was heated under reflux for3 hours. The solution was allowed to cool to room temperature, and thereaction solvent was concentrated and evaporated under reduced pressure.The residue was poured into iced water. The solution was neutralized bythe addition of a sodium hydroxide solution, and the organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (chloroform) to give thetitle compound (0.77 g, 8% yield).

[2545] mp: 192-194° C. (recrystallized from ethyl acetate).

[2546] NMR (CDCl₃) δ: 2.92 (3H, s), 7.46 (1H, dd, J=4.6 Hz, 8.4 Hz),7.85 (1H, dd, J=7.6 Hz, 11.2 Hz), 8.09 (1H, dd, J=8.6 Hz, 11.2 Hz), 8.55(1H, dd, J=1.4 Hz, 4.6 Hz), 8.73 (1H, ddd, J=1.4 Hz, 2.4 Hz, 8.4 Hz),9.73 (1H, d, J=2.2 Hz).

[2547] Elementary Analysis: for C₁₆H₉ClF₂N₄

[2548] Calcd.: C, 58.11; H, 2.74; N, 16.94; Cl, 10.72; F, 11.49.

[2549] Found: C, 58.18; H, 2.83; N, 17.00; Cl, 10.72; F, 11.34.

EXAMPLE 2-203

[2550]6,7-Difluoro-3-methyl-1-(3-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-onedihydrochloride

[2551] To a solution of4-chloro-6,7-difluoro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(0.70 g, 2.12 mmol) in ethanol (40 mL), 6N hydrochloric acid (2 mL, 12.0mmol) was added, and the mixture was heated under reflux for 2.5 days.The solution was allowed to cool to room temperature, and the resultingcrystals were collected by filtration. The crystals were washed withethanol and air dried to give the title compound (0.27 g, 33% yield).

[2552] mp: >300° C.

[2553] NMR (DMSO-d₆) δ: 2.57 (3H, s), 7.74 (1H, dd, J=6.8 Hz, 11.8 Hz),7.89 (1H, dd, J=5.0 Hz, 8.4 Hz), 8.02 (1H, dd, J=9.0 Hz, 11.2 Hz),8.41-8.46 (1H, m), 8.83 (1H, dd, J=1.2 Hz, 5.0 Hz), 9.14 (1H, d, J=2.2Hz), hidden (1H).

EXAMPLE 2-204

[2554]4-Chloro-6,7-difluoro-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2555] A solution of 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-ylamine (5.80g, 33.3 mmol), 2-chloro-4,5-difluorobenzoic acid (5.78 g, 30.0 mmol),copper acetate (II) (0.545 g, 3.00 mmol) and potassium carbonate (4.15g, 30.0 mmol) in N,N-dimethylformamide (30 mL) was heated under refluxunder an argon atmosphere for 2 hours. The solution was allowed to coolto room temperature and poured into water. The solution was made weaklyacidic by the addition of 1N hydrochloric acid, and the resulting crudecrystals were collected by filtration. The crystals were washed withwater and air dried to give crude4,5-difluoro-2-[[3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (6.44 g, 65% yield). A solution of the compound (5.50 g, 16.7 mmol)in phosphorous oxychloride (10 mL, 107 mmol) was heated under reflux for3 hours. The solution was allowed to cool to room temperature, and theresulting residue was poured into iced water. The solution wasneutralized by the addition of a sodium hydroxide solution, and theorganic matter was extracted with chloroform. The extract was washedwith saturated brine and water, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatography(chloroform to 1% methanol/chloroform) to give the title compound (0.88g, 16% yield).

[2556] mp: 226-228° C. (recrystallized from ethyl acetate/methanol).

[2557] NMR (CDCl₃) δ: 2.91 (3H, s), 7.91 (1H, dd, J=7.6 Hz, 11.2 Hz),8.11 (1H, dd, J=8.6 Hz, 11.0 Hz), 8.50 (2H, dd, J=1.6 Hz, 4.8 Hz), 8.72(2H, dd, J=1.6 Hz, 4.8 Hz).

[2558] Elementary Analysis: for C₁₆H₉ClF₂N₄

[2559] Calcd.: C, 58.11; H, 2.74; N, 16.94; Cl, 10.72; F, 11.49.

[2560] Found: C, 58.02; H, 2.80; N, 16.87; Cl, 10.42; F, 11.75.

EXAMPLE 2-205

[2561]6,7-Difluoro-3-methyl-1-(4-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-onedihydrochloride

[2562] To a solution of4-chloro-6,7-difluoro-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(0.80 g, 2.42 mmol) in ethanol (40 mL), 6N hydrochloric acid (2 mL, 12.0mmol) was added, and the mixture was heated under reflux for 6 hours.The solution was allowed to cool to room temperature, and the resultingcrystals were collected by filtration. The crystals were washed withethanol, air dried and recrystallized from ethanol to give the titlecompound (0.51 g, 55% yield).

[2563] mp: 237-240° C. (recrystallized from ethanol).

[2564] NMR (DMSO-d₆) δ: 2.81 (3H, s), 8.14 (1H, dd, J=7.6 Hz, 11.4 Hz),8.27 (1H, dd, J=8.8 Hz, 11.2 Hz), 8.82 (2H, d, J=7.0 Hz), 8.94 (2H, d,J=7.0 Hz), hidden (1H).

[2565] Elementary Analysis: for C₁₆H₁₀F₂N₄O.2HCl

[2566] Calcd.: C, 49.89; H, 3.14; N, 14.54; Cl, 18.41; F, 9.86.

[2567] Found: C, 49.99; H, 3.14; N, 14.69; Cl, 18.04; F, 9.87.

Reference Example 2-81

[2568] 2-Hydrazino-6-methylpyridine

[2569] A mixture of 2-chloro-6-methylpyridine (50.6 g, 397 mmol) andhydrazine hydrate (80 mL, 1.65 mol) was heated under reflux for 20hours. The reaction solution was allowed to cool to room temperature,and excess hydrazine hydrate was evaporated under reduced pressure, andthe residue was poured into water. The solution was made basic by theaddition of a sodium hydroxide solution, and the organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waschilled to crystallize, and the resulting crystals were washed withpetroleum ether to give the title compound (31.0 g, 63% yield).

[2570] mp: 54-56° C.

[2571] NMR (CDCl₃) δ: 2.40 (3H, s), 3.61 (2H, br s), 5.82 (1H, br s),6.53 (1H, d, J=8.0 Hz), 6.54 (1H, d, J=7.4 Hz), 7.39 (1H, dd, J=7.4 Hz,8.0 Hz).

Reference Example 2-82

[2572] 3-Methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-ylamine

[2573] To an ice-cold solution of aminocrotononitrile (20.5 g, 0.25 mol)and 2-hydrazino-6-methylpyridine (31.0 g, 0.252 mol) in ethanol (200mL), acetic acid (30 g, 0.5 mol) was added and the mixture was heatedunder reflux for 2 hours. The reaction solution was allowed to cool toroom temperature, and the reaction solvent was concentrated andevaporated under reduced pressure, and water was added to the residue.The solution was made basic by the addition of an aqueous sodiumhydroxide solution, and the organic matter was extracted with ethylacetate. The extract was washed with saturated brine and water, driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (ethyl acetate) to give the title compound (41.3g, 88% yield).

[2574] mp: 149-150° C. (recrystallized from ethyl acetate).

[2575] NMR (CDCl₃) δ: 2.22 (3H, s), 2.50 (3H, s), 5.34 (1H, s), 5.95(2H, br s), 6.90 (1H, dd, J=0.8 Hz, 7.0 Hz), 7.63 (1H, dd, J=7.0 Hz, 8.4Hz), 7.72 (1H, dd, J=0.8 Hz, 8.4 Hz).

[2576] Elementary Analysis: for C₁₀H₁₂N₄

[2577] Calcd.: C, 63.81; H, 6.43; N, 29.77.

[2578] Found: C, 63.94; H, 6.51; N, 29.90.

EXAMPLE 2-206

[2579] 1-(2-Pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2580] To a solution of4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (14 g, 0.050 mol)in ethanol (600 mL), 6N hydrochloric acid (30 mL) was added and themixture was heated under reflux for 12 hours. The reaction solution wasallowed to cool to room temperature, and concentrated and evaporatedunder reduced pressure. The residue was made basic by addition of anaqueous sodium hydroxide solution, and the organic matter was extractedwith chloroform. The extract was washed with saturated brine and water,dried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue thus obtained was purified by silicagel column chromatography (chloroform:methanol=96:4) to give the titlecompound (10.8 g, 82% yield).

EXAMPLE 2-207

[2581]4-Chloro-3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline

[2582] A solution of3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-ylamine (7.03 g, 37.3mmol), 2-iodobenzoic acid (10.2 g, 41.0 mmol), copper acetate (II)(0.745 g, 4.10 mmol) and potassium carbonate (5.67 g, 41.0 mmol) inN,N-dimethylformamide (30 mL) was heated under reflux under an argonatmosphere for 2 hours. The reaction solution was allowed to cool toroom temperature, and the reaction mixture was poured into water. Thesolution was made weakly acidic by the addition of 1N hydrochloric acid,and the resulting crude crystals were collected by filtration. Thecrystals were washed with water and air dried to give crude2-[[3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid(10.6 g, 92% yield). A solution of the compound (9.5 g, 30.8 mmol) inphosphorous oxychloride (15 mL, 161 mmol) was heated under reflux for 1hour. The reaction solution was allowed to cool to room temperature, andthe residue was poured into iced water. The solution was neutralized bythe addition of a sodium hydroxide solution, and the organic matter wasextracted with chloroform. The extract was washed with saturated brineand water, and dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (chloroform) to give thetitle compound (2.37 g, 25% yield).

[2583] mp: 154° C. (recrystallized from ethyl acetate). NMR (CDCl₃) δ:2.71 (3H, s), 3.01 (3H, s), 7.13 (1H, d, J=7.8 Hz), 7.55-7.63 (1H, m),7.78-7.87 (2H, m), 8.16 (1H, dd, J=1.0 Hz, 8.8 Hz), 8.38-8.43 (1H, m),8.58 (1H, d, J=1.0 Hz, 8.4 Hz), 7.69 (1H, d, J=8.0 Hz).

[2584] Elementary Analysis: for C₁₇H₁₃ClN₄

[2585] Calcd.: C, 66.13; H, 4.24; N, 18.15; Cl, 11.48.

[2586] Found: C, 66.19; H, 4.36; N, 18.25; Cl, 11.36.

EXAMPLE 2-208

[2587]3-Methyl-1-(6-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2588] To a solution of4-chloro-3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(2.00 g, 6.48 mmol) in ethanol (90 mL), 6N hydrochloric acid (3 mL, 18.0mmol) was added and the mixture was heated under reflux for 4 hours. Thereaction solution was allowed to cool to room temperature, and theresulting crystals were collected by filtration. The crystals werewashed with ethanol, air dried, and recrystallized from ethanol to givethe title compound (1.55 g, 82% yield).

[2589] mp: 252° C. (recrystallized from ethanol).

[2590] NMR (DMSO-d₆) δ: 2.60 (3H, s), 2.70 (3H, s), 7.23 (1H, d, J=7.6Hz), 7.29-7.37 (1H, m), 7.66-7.75 (2H, m), 7.83-7.96 (2H, m), 8.21 (1H,dd, J=0.6 Hz, 8.0 Hz), 11.64 (1H, br s).

[2591] Elementary Analysis: for C₁₇H₁₄N₄O

[2592] Calcd.: C, 70.33; H, 4.86; N, 19.30.

[2593] Found: C, 70.29; H, 4.64; N, 19.25.

EXAMPLE 2-209

[2594]6,7-Difluoro-3-methyl-1-(6-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one

[2595] A solution of3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-ylamine (5.65 g, 30.0mmol), 2-chloro-4,5-difluorobenzoic acid (6.93 g, 36.0 mmol), copperacetate (II) (0.545 g, 3.00 mmol) and potassium carbonate (4.15 g, 30.0mmol) in N,N-dimethylformamide (30 mL) was heated under reflux under anargon atmosphere for 2 hours. The solution was allowed to cool to roomtemperature, and the reaction mixture was poured into water. Thesolution was made weakly acidic by the addition of 1N hydrochloric acid,and the resulting crude crystals were collected by filtration. Thecrystals were washed with water and air dried to give crude4,5-difluoro-2-[[3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoicacid (8.18 g, 79% yield). A solution of the compound (7.00 g, 20.3 mmol)in phosphorus oxychloride (9.73 mL, 104 mmol) was heated under refluxfor 30 minutes. The reaction solution was allowed to cool to roomtemperature, and the residue was poured into iced water. The solutionwas neutralized by the addition of a sodium hydroxide solution, and theorganic matter was extracted with chloroform. The extract was washedwith saturated brine and water, dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue thusobtained was purified by silica gel column chromatography (chloroform)to give crude4-chloro-6,7-difluoro-3-methyl-1-(6-methyl-2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline(2.70 g, 39% yield). To a solution of the compound (2.70 g, 36.0 mmol)in ethanol (120 mL), 6N hydrochloric acid (4 mL, 24.0 mmol) was added,and the mixture was heated under reflux for 3 hours. The reactionsolution was allowed to cool to room temperature, and the resultingcrystals were collected by filtration. The crystals were washed withethanol, air dried and recrystallized from ethanol to give the titlecompound (1.68 g, 66% yield).

[2596] mp: 301-302° C. (recrystallized from ethanol).

[2597] NMR (CDCl₃:CF₃CO₂D=50:1) δ: 2.75 (6H, s), 7.23 (1H, d, J=7.4 Hz),7.37 (1H, dd, J=6.2 Hz, 9.8 Hz), 7.79 (1H, d, J=8.0 Hz), 7.93 (1H, dd,J=7.4 Hz, 8.0 Hz), 8.28 (1H, dd, J=8.2 Hz, 10.4 Hz), 10.85 (1H, br s).

[2598] Elementary Analysis: for C₁₇H₁₂F₂N₄O

[2599] Calcd.: C, 62.57; H, 3.71; N, 17.17; F, 11.64.

[2600] Found: C, 62.55; H, 3.58; N, 17.09; F, 11.61.

[2601] Structures of the chemical compounds prepared in Examples 2-1 to2-209 are shown in the following Tables 7 to 14. TABLE 7

Sub- Example stituent of Number R^(1a) R^(3a) X Ring B^(a) 2-1  Me 2-PyCl 2-2  Me 2-Py NH₂ 2-3  Me 2-Py NH₂ 2-4  Me 2-Py MeNH 2-5  Me 2-Pycyclopropyl-NH 2-6  Me 2-Py ^(n)PrNH 2-7  Me 2-Py ^(n)BuNH 2-8  Me 2-PyMe₂N 2-9  Me 2-Py ^(n)Pr(Me)N 2-10  Me 2-Py ^(n)Bu(Me)N 2-11  Me 2-Pymorpholinyl 2-15  Me 2-Py MeO 2-16  Me 2-Py EtO 2-17  Me 2-Py ^(n)PrO2-18  Me 2-Py ^(i)PrO 2-19  Me 2-Py ^(n)BuO 2-20  Me 2-Py ^(i)BuO 2-21 Me 2-Py cyclopentyloxy 2-22  Me 2-Py cyclohexyloxy 2-23  Me 2-Py PhCH₂O2: NO₂ 2-25  Me 2-Py ^(i)PrS 2-26  Me 2-Py ^(i)PrSO 2-27  Me 2-Py^(n)PrS 2-28  Me 2-Py ^(n)PrSO 2-29  Me 2-Py Cl 1: Me 2-30  Me 2-Py NH₂1: Me 2-32  Me 2-Py Cl 2: Me 2-33  Me 2-Py NH₂ 2: Me 2-35  Me 2-Py Cl 4:Me 2-36  Me 2-Py NH₂ 4: Me 2-37  Me 2-Py NH₂ 4: Me 2-39  Me 2-Py Cl 2:CF₃ 2-41  Me 2-Py Cl 2: MeO 2-42  Me 2-Py NH₂ 2: MeO 2-44  Me 2-Py Cl 4:MeO 2-45  Me 2-Py NH₂ 4: MeO 2-46  Me 2-Py Cl 2, 3: MeO 2-47  Me 2-PyNH₂ 2, 3: MeO 2-49  Me 2-Py Cl 2: MeS 2-53  Me 2-Py Cl 2: NO₂ 2-57  Me2-Py Cl 3: NO₂ 2-60  Me 2-Py Cl 1: CO₂Me 2-63  Me 2-Py Cl 2: CO₂Me 2-66 Me 2-Py Cl 3: CO₂Me 2-70  Me 2-Py Cl 2: Cl 2-71  Me 2-Py NH₂ 2: Cl 2-73 Me 2-Py Cl 3: Cl 2-75  Me 2-Py Cl 2, 3: Cl 2-78  Me 2-Py Cl 1: F 2-80 Me 2-Py Cl 2: F 2-82  Me 2-Py Cl 3: F 2-84  Me 2-Py Cl 4: F 2-86  Me2-Py Cl 2: Br 2-88  Me 2-Py Cl 1, 2: F 2-90  Me 2-Py Cl 2, 3: F 2-94  Me2-Py ^(n)PrO 2, 3: F 2-95  Me 2-Py ^(i)PrO 2, 3: F 2-96  Me 2-Py Cl 2:F, 3: Cl 2-98  Me 2-Py Cl 2: Cl, 3: F 2-100 Me 2-Py H 2-101 Me 2-Py Me2-102 Me 2-Py Et 2-103 Me 2-Py ^(n)Pr 2-104 Me 2-Py ^(n)Bu 2-105 Me 2-Py^(i)Bu 2-106 Me 2-Py ^(n)Pentyl 2-107 Me 2-Py CN 2-108 Me 2-Py CONH₂2-109 Me 6-Cl-2-Py Cl 2-111 Me 6-EtO-2-Py Cl 2-113 Me 5-Cl-2-Py Cl 2-115Me 5-Me-2-Py Cl 2-116 Me 5-Me-2-Py NH₂ 2-118 Me 3-Me-2-Py Cl 2-119 Me3-Me-2-Py NH₂ 2-121 Me 6-EtO-2-Py Cl 1: Me 2-123 Me 3-Me-2-Py Cl 1: Me2-124 Me 3-Me-2-Py NH₂ 1: Me 2-126 Me 6-MeO-2-Py Cl 4: Me 2-127 Me6-MeO-2-Py NH₂ 4: Me 2-128 Me 6-EtO-2-Py Cl 4: Me 2-129 Me 6-EtO-2-PyNH₂ 4: Me 2-131 Me 5-Me-2-Py Cl 4: Me 2-132 Me 5-Me-2-Py NH₂ 4: Me 2-133Me 3-Me-2-Py Cl 4: Me 2-134 Me 3-Me-2-Py NH₂ 4: Me 2-136 Me 3-Py Cl2-137 Me 3-Py NH₂ 2-139 Me 3-Py MeO 2-140 Me 4-Py Cl 2-141 Me 4-Py NH₂2-142 Me 4-Py Me₂N 2-144 Me 2-Pyrimidinyl Cl 2-145 Me 2-Pyrimidinyl NH₂2-147 Me 4,6-Me- Cl Pyrimidinyl 2-149 Me 1,3-thiazol-2-yl Cl 2-150 Me1,3-thiazol-2-yl NH₂ 2-152 Me 2-quinolinyl Cl 4: Me 2-153 Me2-quinolinyl NH₂ 4: Me 2-157 H 2-Py Cl 2-158 H 2-Py NH₂ 2-160 H 2-Py Cl2: Cl 2-162 H 2-Py Cl 1: F 2-164 H 2-Py Cl 2: F 2-166 CF₃ 2-Py Cl 2-168CH₂Br 2-Py Cl 2-169 Et 2-Py Cl 2-170 Et 2-Py NH₂ 2-172 ^(i)Pr 2-Py Cl2-175 CH₂COOMe 2-Py Cl 2-179 COOEt 2-Py Cl 2-183 4-MeOPh 2-Py Cl 2-1844-MeOPh 2-Py NH₂ 2-186 Me 2-Py-CH₂ Cl 2-187 Me 2-Py-CH₂ NH₂ 2-188 Me2-Py-CH₂ Me₂N 2-190 Me 2-Py-CH₂ MeO 2-198 H 2-Py Cl 2,3: F 2-200 Et 2-PyCl 2,3: F 2-202 Me 3-Py Cl 2,3: F 2-204 Me 4-Py Cl 2,3: F 2-207 H 2-PyCl

[2602] TABLE 11

Example Substituent of Number R^(1a) R^(2a) R^(3a) X Ring A 2-12  Me H2-Py O 2-13  Me H 2-Py O 2-14  Me Me 2-Py O 2-24  Me H 2-Py S 2-31  Me H2-Py O 1: Me 2-34  Me H 2-Py O 2: Me 2-38  Me H 2-Py O 4: Me 2-40  Me H2-Py O 2: CF₃ 2-43  Me H 2-Py O 2: MeO 2-48  Me H 2-Py O 2, 3: Me0 2-50 Me H 2-Py O 2: MeS 2-51  Me H 2-Py O 2: MeSO 2-52  Me H 2-Py O 2: MeSO₂2-54  Me H 2-Py O 2: NO₂ 2-55  Me H 2-Py O 2: NH₂ 2-56  Me H 2-Py O 2:Me₂N 2-58  Me H 2-Py O 3: NO₂ 2-59  Me H 2-Py O 3: NH₂ 2-61  Me H 2-Py O1: CO₂Me 2-62  Me H 2-Py O 1: CO₂H 2-64  Me H 2-Py O 2: CO₂Me 2-65  Me H2-Py O 2: CO₂H 2-67  Me H 2-Py O 3: CO₂Me 2-68  Me H 2-Py O 3: CO₂H2-69  Me H 2-Py O 1: Cl 2-72  Me H 2-Py O 2: Cl 2-74  Me H 2-Py O 3: Cl2-76  Me H 2-Py O 2, 3: Cl 2-77  Me H 2-Py O 2, 4: Cl 2-79  Me H 2-Py O1: F 2-81  Me H 2-Py O 2: F 2-83  Me H 2-Py O 3: F 2-85  Me H 2-Py O 4:F 2-87  Me H 2-Py O 2: Br 2-89  Me H 2-Py O 1, 2: F 2-91  Me H 2-Py O 2,3: F 2-92  Me H 2-Py O 2, 3: F 2-93  Me ^(n)Pr 2-Py O 2, 3: F 2-97  Me H2-Py O 2: F, 3: Cl 2-99  Me H 2-Py O 2: Cl, 3: F 2-110 Me H 6-Cl-2-Py O2-112 Me H 6-EtO-2-Py O 2-114 Me H 5-Cl-2-Py O 2-117 Me H 5-Me-2-Py O2-120 Me H 3-Me-2-Py O 2-122 Me H 6-EtO-2-Py O 1: Me 2-125 Me H3-Me-2-Py O 1: Me 2-130 Me H 6-EtO-2-Py O 4: Me 2-135 Me H 3-Me-2-Py O4: Me 2-138 Me H 3-Py O 2-143 Me H 4-Py O 2-146 Me H 2-Pyrimidinyl O2-148 Me H 4,6-Me-Pyrimidinyl O 2-151 Me H 1,3-thiazol-2-yl O 2-154 Me H2-quinolinyl O 4: Me 2-159 H H 2-Py O 2-161 H H 2-Py O 2: Cl 2-163 H H2-Py O 1: F 2-165 H H 2-Py O 2: F 2-167 CF₃ H 2-Py O 2-171 Et H 2-Py O2-173 ^(i)Pr H 2-Py O 2-174 ^(i)Bu H 2-Py O 2-176 CH₂COOMe H 2-Py O2-177 CH₂COOH H 2-Py O 2-178 CH₂CONH₂ H 2-Py O 2-180 COOEt H 2-Py O2-181 COOH H 2-Py O 2-182 Ph H 2-Py O 2-185 4-MeOPh H 2-Py O 2-189 Me H2-Py-CH₂ O 2-191 Me H 3-Py-CH₂ O 2-192 Me H 4-Py-CH₂ O 2-199 H H 2-Py O2,3: F 2-201 Et H 2-Py O 2,3: F 2-203 Me H 3-Py O 2,3: F 2-205 Me H 4-PyO 2,3: F 2-206 H H 2-Py O 2-208 Me H 6-Me-2-Py O 2-209 Me H 6-Me-2-Py O2,3: F

[2603] TABLE 14

Example Number X Ring B^(a) 2-155 Cl

2-156 OH

2-193 OH

2-194 OH

2-195 OH

2-196 Cl

2-197 OH

Formulation Example 2-1

[2604] (1) The compound obtained in Example 2-1 10.0 g (2) Lactose 60.0g (3) Cornstarch 35.0 g (4) Gelatin  3.0 g (5) Magnesium stearate  2.0 g

[2605] A mixture of the compound obtained in Example 2-1 (10.0 g),lactose (60.0 g), and cornstarch (35.0 g) was sieved through a 1 mm meshsieve by the use of an aqueous solution of 10 wt % gelatin (30 ml, 3.0 gas gelatin), and the resulting granules were dried at 40° C., and sievedonce again. The granules thus obtained were mixed with magnesiumstearate (2.0 g) and compressed. The core tablet thus obtained wassugarcoated by the use of an aqueous suspension containing sucrose,titanium dioxide, talc and gum acacia. The coated tablets were glazedwith beeswax to give 1000 coated tablets.

Formulation Example 2-2

[2606] (1) The compound obtained in Example 2-1 10.0 g (2) Lactose 70.0g (3) Cornstarch 50.0 g (4) Soluble starch  7.0 g (5) Magnesium stearate 3.0 g

[2607] A mixture of the compound obtained in Example 2-1 (10.0 g) andmagnesium stearate (3.0 g) was granulated by the use of an aqueoussolution of soluble starch (70 ml, 7.0 g as soluble starch), and theresulting granules were dried, and mixed with lactose (70.0 g) andcornstarch (50.0 g). The mixture was compressed to give 1000 tablets.

Experimental Example

[2608] The gene manipulation methods described in Experimental Examplebelow are carried out in accordance with the methods described inManiatis et al., Molecular Cloning (ColdSpring Harbor Laboratory, 1989)or the methods described in the protocols attached to reagents.

[2609] Preparation of Microsome Fractions

[2610] Preparation of Human COX-1 cDNA Recombinant Baculovirus

[2611] A 1.8 kb DNA fragment containing human COX-1 cDNA (FASEB J.,vol.5 (9), p.2304-2312 (1991)) prepared by the PCR method was insertedinto plasmid pFASTBAC1 (CIBCOBRL) to obtain a plasmid pFBCOX1.

[2612] Using the plasmid pFBCOX1 and BAC-TO-BAC Baculovirus ExpressionSystem (GIBCOBRL), a virus stock BAC-COX1 of the recombinant baculoviruswas prepared.

[2613] Preparation of Microsome Fractions from COX-1 Expressing InsectCells

[2614] Sf-21 cells were inoculated in 125 mL of Sf-900 II SFM medium(GIBCOBRL) at a concentration of 1×10⁶ cells/mL, and the medium wasincubated at 27° C. for 24 hours. 0.75 mL of the virus stock BAC-COX1 ofthe recombinant baculovirus was added thereto, and the mixture wasincubated further for 72 hours. The cells were separated from the mediumby centrifugation (3000 rpm, 10 min), and washed with PBS twice. Thecells were suspended in 10 mL of a Lysis buffer (0.1M Tris-HCl (pH 7.4),5 mM EDTA), and were treated with a homogenizer (POLYTRON) three timesat 20000 rpm for 20 seconds so that the cells were crushed. Thesupernatant obtained after centrifugation (2000 rpm, 10 minutes) wasfurther centrifuged (40000 rpm, 45 minutes) to give a precipitate, whichwas resuspended in a Lysis buffer (0.1M Tris-HCl (pH 7.4), 5 mM EDTA),and the suspension was stored at −80° C.

[2615] Preparation of Human COX-2 cDNA Recombinant Baculovirus

[2616] A 1.8 kb DNA fragment containing human COX-2 cDNA (Proc. Natl.Acad. Sci. U.S.A., vol.89 (16), p.7384-7388 (1992)) prepared by the PCRmethod was inserted into plasmid pFASTBAC1 (CIBCOBRAL) to obtain aplasmid pFBCOX2.

[2617] Using the plasmid pFBCOX2 and BAC-TO-BAC Baculovirus ExpressionSystem (GIBCOBRAL), a virus stock BAC-COX2 of the recombinantbaculovirus was prepared.

[2618] Preparation of Microsome Fractions from COX-2 Expressing InsectCells

[2619] Sf-21 cells were inoculated in 125 mL of LSf-900 II SFM medium(GIBCOBRAL) at a concentration of 1×10⁶ cells/mL, and the medium wasincubated at 27° C. for 24 hours. 0.75 mL of the virus stock BAC-COX2 ofthe recombinant baculovirus was added thereto, and was incubated furtherfor 72 hours. The cells were separated from the medium by centrifugation(3000 rpm, 10 min), and washed with PBS twice. The cells were suspendedin 10 mL of a Lysis buffer (0.1M Tris-HCl (pH 7.4), 5 mM EDTA), and weretreated with a homogenizer (POLYTRON), three times at 20000 rpm for 20seconds so that the cells were crushed. The supernatant thus obtainedafter centrifugation (2000 rpm, 10 minutes) was further centrifuged(40000 rpm, 45 minutes) to obtain a precipitate, which was resuspendedin a Lysis buffer (0.1M Tris-HCl (pH 7.4), 5 mM EDTA), and thesuspension was stored at −80° C.

Experimental Example 2-1

[2620] Determination of COX-1 and COX-2 inhibitory activities

[2621] To a mixture of 20 mL of a reaction buffer previouslyconcentrated 10 times (1M Tris-HCl (pH 8.0), 50 mM EDTA, 1.0% Tween 20,50 mM luminol, 100 mM hematin), 20 mL of the microsome fractions (COX-1:40 mg, COX-2: 20 mg), and 55 mL of distilled water, a sample compounddissolved in DMF (5 mL) was added, and the mixture was left at 37° C.for 25 minutes. The reaction was started by the addition of 20 mMarachidonic acid (100 mL), and chemiluminescence amount during the10-second period after the addition of arachidonic acid was determinedby the use of Lumistar (BMG Lab technologies, GmbH). The inhibition ratewas calculated, regarding that the enzyme activity when DMF (5 mL) wasadded was 100%, and the enzyme activity when 4 mM flurbiprofen (5 mL)was added was 0%. The results are shown in Table 15. TABLE 15 CompoundRepression rate IC₅₀ (μM) (Example No.) COX-1 COX-2 2-6 21.7 65.1  2-177.28 49.2  2-21 4.21 86.0  2-61 2.00 44.0  2-91 0.527 0.295  2-92 0.6770.465  2-99 0.263 0.213  2-161 0.600 0.360  2-79 7.80 3.70  2-159 2.661.37

[2622] The results in Table 15 indicate that the compound (I) of thepresent invention has an excellent cyclooxygenase inhibition activity.

Experimental Example 2-2

[2623] Anti-Inflammatory Activity

[2624] Carrageenin Edema Method

[2625] Male SD-rats (6 weeks old, CLEA Japan) were used (1 group, n=6).The Carrageenin edema method was performed according to the method ofWinter et. al., (Proc. Soc. Exp. Biol. Med., vol.111, p.544-547, 1962).After the volume of right hind limb plantar of the rat was determined, asample was orally administered (1.0 mL, b.w.), and immediately water wasorally administered in an amount of 5 mL/rat. Meanwhile, only thesolvent of the sample was orally administered to rats in control. After1 hour, a solution of 1% carrageenin in saline (0.05 mL) was injectedinto the right hind limb plantar subcutaneously to induce edema. After 2and 3 hours later from the injection, volumes of the right hind limbplantar were determined. The repression rate (%) of the sample wascalculated by comparing the difference of the volumes of the plantarbefore the carrageenin shot and 2 and 3 hours after the shot between thesample groups and the control groups. The results are shown in Table 16.TABLE 16 Repression rate (%) Compound Dosage 10 mg/kg (Example No.) 2 hrlater 3 hr later 2-6 43** 35**  2-17 45** 37**  2-21 52** 45**  2-6136*  28*   2-91 51** 42**  2-99 46** 41**  2-161 33** 33**  2-79 37**33**  2-159 50** 39 

[2626] The results in Table 16 indicate that the compound (I) of thepresent invention has an excellent anti-inflammatory activity.

Experimental Example 2-3

[2627] Analgesic Activity

[2628] Acetic Acid Rising Method

[2629] Male ICR-mice (5 weeks old, CLEA Japan) were used (1 group,n=10), and a sample was orally administered (0.2 mL/10 g, b.w.). After30 minutes, 0.6% acetic acid solution was injected to miceintraperitoneally (0.1 mL/10 g, b.w.), and the mice were immediatelytransferred into an observation cage made of a transparent acrylicresin. The number of rising and stretching during the following periodof 20 minutes was counted. The repression rate (%) was calculated bycomparing the average numbers between the sample groups and the controlgroups. The results are shown in Table 17. TABLE 17 Compound Repressionrate (%) (Example No.) Dosage 10 mg/kg 2-6 57**  2-17 49*   2-21 56** 2-61 75**  2-91 65**  2-99 39*   2-161 74**  2-79 38**  2-159 69**

[2630] The results in Table 17 indicate that the compound (I) of thepresent invention has an excellent analgesic activity.

Experimental Example 2-4

[2631] Antipyretic Activity in Yeast-Induced Pyrexia

[2632] Antipyretic activity was determined using male SD originmale-rats (7 weeks old, CLEA Japan, 1 group: n=6), according to themethod of winter et. al. (J. Pharmacol. Exp. Ther., vol.138, p.405,1963). Before 16 hours from measurement of body temperature, asuspension of 15% yeast in saline was injected subcutaneously (10 mL/kg,b.w.) into the rats to induce fever, and simultaneously supply of foodwas terminated while water was made available all the time. Each of therats was raised separately. After 16 hours from the yeast shot, athermistor terminal was inserted at an about 4 cm depth into rectumevery hour, and the body temperatures after 30 seconds were recorded.After 18 hours, rats developing fevers consistently were selected, and asample was orally administered to the rats (5 mL/kg, b.w.), while to thecontrol, only the solvent was administered. After the administration,body temperatures were measured every hour for a period of 6 hours, andthe maximum difference in body temperature between the rats in thesample group and in the control group were determined as Δ (° C.). Theresults are shown in Table 18. TABLE 18 Compound Δ (° C.) (Example No.)Dosage 10 mg/kg 2-6 0.8**  2-17 1.5**  2-18 1.7**  2-21 1.8**  2-791.4**  2-91 1.5**  2-161 1.4**  2-159 1.8**

[2633] The results in Table 18 indicate that the compound (I) of thepresent invention has an excellent antipyretic activity.

Experimental Example 2-5

[2634] Anti-Adjuvant-Arthritic Activity

[2635] Male SD origin male-rats (6 weeks old, CLEA Japan, 1 group: n=7)were used. The adjuvant arthritis method was conducted according to themethod of Newbould B. B. et. al., (Brit. J. Pharmacol. Chemother.,vol.21, p.127, 1963). Complete Freund's adjuvant (a suspension of killedtubercule bacillus in liquid paraffin at a concentration of 0.5%, 0.05mL) was injected into the right hind limb footpad intracutaneouly toinduce multiple arthritis. Samples were administered orally (10 mg/kg,b.w.), once a day for 14 days from the day before the injection day 0 today 13. Volume of the left hind limb (not injected) was determined bythe foot-volume measurement apparatus manufactured by Ugo Basile, on theday just before the adjuvant shot (Day 0), Day 10 and Day 14, andrepression rate (%) was calculated comparing the values between thesample group and the control group. The results are shown in Table 19.TABLE 19 Compound Repression rate (%) (Example No.) Dosage 10 mg/kg 2-17 61*   2-13 47   2-31 56   2-83 65*   2-91 76**

[2636] The results in Table 19 indicate that the compound (I) of thepresent invention has an excellent anti-inflammatory activity.

Experimental Example 2-6

[2637] Disorder of Gastric Mucosa

[2638] Male SD origin male-rats (7 weeks old, CLEA Japan) were used.After 24 hours from the termination of food supply, samples were orallyadministered (5 mL/kg, b.w.). After 5.5 hours, Evan's Blue (0.5% Evan'sBlue/saline) was injected intravenously (1 mL/rat) under no anesthesia.After 30 minutes from the shot, the stomach (with esophagus and duodenumof 1.5 to 2 cm length) was removed by celiotomy, and subsequently, theesophagus terminal was closed with a clip, and a 8 mL of 1% formalinsolution was injected into the stomach through the duodenum, which wasalso closed with a clip after the injection. The stomach was leftcontacting with the 1% formalin solution for more than 10 minutes, andsubsequently cut open from duodenum along the greater curvature ofstomach. The stomach was washed and spread on a filter paper, and thelength of each of the spots dyed by Evan's Blue (hemorrhagic portion:mucosal ablation to ulcer) was measured under a stereomicroscope, andthe total length (mm) was calculated by a counter and recorded. Theresults are shown in Table 20. TABLE 20 Compound (Example No.) Totallength of dyed spots (mm)  2-91 0 (1000 mg/kg)  2-92 0 (1000 mg/kg) 2-79 0 (300 mg/kg)  2-159 0 (300 mg/kg)

Experimental Example 2-7

[2639] Disorder of Mucosa of Small Intestine

[2640] Male SD origin male-rats (7 weeks old, CLEA Japan) were used. Tothe rats freely fed, samples were administered orally (5 mL/kg, b.w.).After 5.5 hours from the administration, Evan's Blue (0.5% Evan'sBlue/saline) was injected (1 mL/rat) intravenously under no anesthesia.After 30 minutes from the shot, the intestine was removed by celiotomyand the area thereof facing mesentery was cut open. After removal ofintestinal content, the spots in the intestine dyed by Evan's Blue weremeasured under a stereomicroscope, and the total length (mm) of thespots was determined by a counter and recorded. The results are shown inTable 21. TABLE 21 Compound (Example No.) Total length of dyed spots(mm)  2-12 0 (100 mg/kg)  2-17 0 (300 mg/kg)  2-40 0 (100 mg/kg)  2-92 0(300 mg/kg)  2-79 0 (300 mg/kg)  2-159 0 (300 mg/kg)

INDUSTRIAL APPLICABILITY

[2641] The compound (I) of the present invention or the salt thereof (1)suppresses Th2 immune responses by inhibiting production of IL-4, IL-5and IgE associated with allergic reactions, and consequently controlsthe balance of Th1 and Th2, and thus provides a novel drug forprevention and/or treatment of allergic diseases, (2) inhibits bothcyclooxgenases-1 and -2, and thus has excellent anti-inflammatory,analgesic, and antipyretic activities. It has extremely low possibilityof inducing gastrointestinal disorders, compared with the conventionalanti-inflammatory and analgesic drugs. Therefore, clinically usefuldrugs as an anti-inflammatory and analgesic drug are provided.Furthermore, the compound (I) of the present invention or the saltthereof is excellent in pharmacokinetics and also in solubility inwater.

1. A pharmaceutical composition for selectively inhibiting Th2 immuneresponses, which comprises a condensed pyrazole derivative representedby the formula (I):

wherein R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted or acarboxyl group which may be optionally esterified or amidated; R² isunsubstituted, or a hydrogen atom or a hydrocarbon group which may beoptionally substituted; R³ is a heterocyclic group which may beoptionally substituted; X, Y and Z are, respectively, hydrogen, halogen,nitrile, a hydrocarbon group which may be optionally substituted, acarboxyl group which may be optionally esterified or amidated, an acylgroup which may be optionally substituted, —NR⁴R⁵, an oxygen atom, —OR⁴,a sulfur atom, or —SR⁴ (R⁴ and R⁵ are, respectively, a hydrogen atom, ahydrocarbon group which may be optionally substituted, a heterocyclicgroup which may be optionally substituted, or both may bind each otherto form a cyclic amino group or a heterocyclic group with the nitrogenatom bound thereto), or X and Y may bind each other to form ring A, or Yand Z may bind each other to form ring B; bond portions indicated byboth solid and broken lines are either a single bond or a double bond,and bond portions indicated by a broken lines are either a single bondor unsubstituted; ring A is a homocyclic or a heterocyclic 5- to7-membered ring which may be optionally substituted; ring B is ahomocyclic or a heterocyclic 5- to 7-membered ring which may beoptionally substituted; and n is an integer of 0 or 1, or a saltthereof.
 2. A pharmaceutical composition for inhibiting cyclooxygenase,which comprises a condensed pyrazole derivative represented by theformula (I):

wherein R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted or acarboxyl group which may be optionally esterified or amidated; R² isunsubstituted, or a hydrogen atom or a hydrocarbon group which may beoptionally substituted; R³ is a heterocyclic group which may beoptionally substituted; X, Y and Z are, respectively, hydrogen, halogen,nitrile, a hydrocarbon group which may be optionally substituted, acarboxyl group which may be optionally esterified or amidated, an acylgroup which may be optionally substituted, —NR⁴R⁵, an oxygen atom, —OR⁴,a sulfur atom or —SR⁴ (R⁴ and R⁵ are, respectively, a hydrogen atom, ahydrocarbon group which may be optionally substituted, a heterocyclicgroup which may be optionally substituted, or both may bind each otherto form with the nitrogen atom bound thereto a cyclic amino group or aheterocyclic group), or X and Y may bind each other to form ring A, or Yand Z may bind each other to form ring B; bond portions indicated byboth solid and broken lines are either a single bond or a double bond,and bond portions indicated by a broken line are either a single bond orunsubstituted; ring A is a homocyclic or heterocyclic 5- to 7-memberedring which may be optionally substituted; ring B is a homocyclic orheterocyclic 5- to 7-membered ring which may be optionally substituted;and n is an integer of 0 or 1, or a salt thereof.
 3. The pharmaceuticalcomposition according to claim 1 or 2, wherein R² is unsubstituted or ahydrogen atom, and X and Y may bind each other to form ring A.
 4. Thepharmaceutical composition according to claim 3, wherein R³ is anunsaturated heterocyclic group containing only one nitrogen atom as thehetero atom which may be optionally substituted and n is
 0. 5. Thepharmaceutical composition according to claim 1 or 2, wherein Y and Zform ring B, and a homocyclic or heterocyclic 5- to 7-membered ringwhich may be optionally substituted as ring B.
 6. The pharmaceuticalcomposition according to claim 1 or 2, wherein the hydrocarbon groups ofR¹ and R² are, respectively, an aliphatic hydrocarbon group, a saturatedmonocyclic hydrocarbon group or an aromatic hydrocarbon group.
 7. Thepharmaceutical composition as claimed in claim 6, wherein thehydrocarbon groups of R¹ and R² are, respectively, an alkyl group, analkenyl group, an alkynyl group, a cycloalkyl group or an aryl group,each of the groups having 1 to 16 carbons.
 8. The pharmaceuticalcomposition according to claim 1 or 2, wherein the homocyclic orheterocyclic groups of ring A or ring B are a group of a saturatedmonocyclic hydrocarbon, a benzene ring, a pyridine ring or a thiophenering.
 9. The pharmaceutical composition according to claim 1 or 2,wherein X is a hydrogen atom, an oxygen atom, —OR⁴ (R⁴ has the samemeaning as described in claim 1) or a hydrocarbon group which may beoptionally substituted.
 10. The pharmaceutical composition according toclaim 1 or 2, wherein Y is COR⁴ or COOR⁴ (R⁴ is as defined in claim 1).11. The pharmaceutical composition according to claim 1 or 2, wherein Zis a hydrogen atom, an oxygen atom, OR⁴ (R⁴ is as defined in claim 1),or a hydrocarbon group which may be optionally substituted.
 12. Apharmaceutical composition for inhibiting cyclooxygenase, whichcomprises a pyrazoloquinoline derivative represented by the formula(Ia):

wherein R^(1a) is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, or a carboxyl group which may be optionallyesterified or amidated; R^(2a) is unsubstituted, or a hydrogen atom or ahydrocarbon group which may be optionally substituted; R^(3a) is aheterocyclic group which may be optionally substituted; X^(a) ishydrogen, halogen, nitrile, a hydrocarbon group which may be optionallysubstituted, a carboxyl group which may be optionally esterified oramidated, an acyl group which may be optionally substituted,—NR^(4a)R^(5a), an oxygen atom, —OR^(4a), a sulfur atom or —SR^(4a)(R^(4a) and R^(5a) are, respectively, a hydrogen atom, a hydrocarbongroup which may be optionally substituted, or both may bind each otherto form a cyclic amino group or a heterocyclic group with the nitrogenatom bound thereto); bond portions indicated by both solid and brokenlines are either a single bond or a double bond, and bond portionsindicated by a broken line are either a single bond or unsubstituted;ring B^(a) is a homocyclic or heterocyclic 5- to 7-membered ring whichmay be optionally substituted; and m is an integer of 0 or 1, or a saltthereof.
 13. The pharmaceutical composition according to claim 1,wherein the pharmaceutical composition is a preventive and/ortherapeutic agent for diseases caused by or associated with immunemalfunction.
 14. The pharmaceutical composition according to claim 1,wherein the pharmaceutical composition is a preventive and/ortherapeutic agent for graft rejection responses.
 15. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical compositionis a preventive and/or therapeutic agent for graft versus host diseases.16. The pharmaceutical composition according to claim 1, wherein thepharmaceutical composition is a preventive and/or therapeutic agent forallergic diseases.
 17. The pharmaceutical composition according to claim1, wherein the pharmaceutical composition is a Th1/Th2 balanceregulator.
 18. The pharmaceutical composition according to claim 2,wherein the pharmaceutical composition is a preventive and/ortherapeutic agent for inflammatory diseases.
 19. The pharmaceuticalcomposition according to claim 2, wherein the pharmaceutical compositionis a preventive and/or therapeutic agent for arthritis.
 20. Thepharmaceutical composition according to claim 2, wherein thepharmaceutical composition is a preventive and/or therapeutic agent forrheumatism.
 21. The pharmaceutical composition according to claim 2,wherein the pharmaceutical composition is a preventive and/ortherapeutic agent for chronic rheumatoid arthritis.
 22. A compoundrepresented by the formula (I′):

wherein R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted or acarboxyl group which may be optionally esterified or amidated; R² isunsubstituted, or a hydrogen atom or a hydrocarbon group which may beoptionally substituted; R^(3′) is an unsaturated heterocyclic groupcontaining only one nitrogen atom as the hetero atom, which may beoptionally substituted; X′, Y′, and Z′ are, respectively, hydrogen,halogen, nitrile, a hydrocarbon group which may be optionallysubstituted, a carboxyl group which may be optionally esterified oramidated, an acyl group which may be optionally substituted, —CON₃,—NR⁴R⁵, ═N—N═R⁴, —N₃, an oxygen atom, —OR⁴, a sulfur atom or —SR⁴ (R⁴and R⁵ are, respectively, a hydrogen atom, a hydrocarbon group which maybe optionally substituted, a heterocyclic group which may be optionallysubstituted, or both may bind each other to form a cyclic amino group ora heterocyclic group with the nitrogen atom bound thereto), or X′ and Y′may bind each other to form ring A′, while either X′ or Z′ is an oxygenatom or —OR⁴; bond portions indicated by both solid and broken lines areeither a single bond or a double bond, and a bond portion indicated by abroken line is either a single bond or unsubstituted; and ring A′ is ahomocyclic or heterocyclic 5- to 7-membered ring which may be optionallysubstituted, or a salt thereof.
 23. The compound according to claim 22,wherein R¹ and R² are an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, or an aryl group, each of the groups having 1to 16 carbons, or a salt thereof.
 24. The compound according to claim22, wherein ring A′ is a saturated monocyclic hydrocarbon or a benzenering, or a salt thereof.
 25. The compound according to claim 22, whereinthe heterocyclic group of R³′ is a nitrogen-containing aromatic6-membered heterocyclic group, or a salt thereof.
 26. The compoundaccording to claim 22, wherein R³′ is 2-pyridinyl which may besubstituted by (1) a halogen atom, (2) a lower alkyl group, (3) acycloalkyl group, (4) a lower alkynyl group, (5) a lower alkenyl group,(6) an aralkyl group, (7) an aryl group, (8) a lower alkoxy group, (9)an aryloxy group, (10) a lower alkanoyl group, (11) an arylcarbonyl,(12) a lower alkanoyloxy group, (13) an arylcarbonyloxy group, (14) acarboxyl group, (15) a lower alkoxycarbonyl group, (16) anaralkyloxycarbonyl, (17) a carbamoyl group, (18) a mono-, di- ortri-halogeno-lower alkyl group, (19) an amidino group, (20) an aminogroup, (21) a mono-lower alkylamino group, (22) a di-lower alkylaminogroup, (23) a 3- to 6-membered cyclic amino group which may contain 1 to3 atoms selected from the group consisting of oxygen, sulfur andnitrogen atoms as the hetero atoms, as well as carbon atoms and onenitrogen atom, (24) an alkylenedioxy group, (25) a hydroxyl group, (26)a nitro group, (27) a cyano group, (28) a mercapto group, (29) a sulfogroup, (30) a sulfino group, (31) a phosphono group, (32) a sulfamoylgroup, (33) a monoalkylsulfamoyl group, (34) a dialkylsulfamoyl group,(35) an alkylthio group, (36) an arylthio group, (37) a loweralkylsulfinyl group, (38) an arylsulfinyl group, (39) a loweralkylsulfonyl group, or (40) an arylsulfonyl group, or a salt thereof.27. The compound according to claim 22, wherein X′ is a hydrogen atom,an oxygen atom, OR⁴ (R⁴ has the same meaning as described in claim 22)or a hydrocarbon group which may be optionally substituted by (1) ahalogen atom, (2) a nitro group, (3) a cyano group, (4) a hydroxylgroup, (5) a lower alkyl group which may be optionally halogenated, (6)a lower alkoxy group, (7) an amino group, (8) a mono-lower alkylaminogroup, (9) a di-lower alkylamino group, (10) a carboxyl group, (11) alower alkyl-carbonyl group, (12) a lower alkoxy-carbonyl group, (13) acarbamoyl group, (14) a mono-lower alkylcarbamoyl group, (15) a di-loweralkylcarbamoyl group, (16) an arylcarbamoyl group, (17) an aryl group,(18) an aryloxy group or (19) a lower alkylcarbonylamino group which maybe optionally halogenated, or a salt thereof.
 28. The compound accordingto claim 22, wherein Y′ is COR⁴ or COOR⁴ (R⁴ is as defined in claim 22),or a salt thereof.
 29. The compound according to claim 22, wherein Z′ isa hydrogen atom, an oxygen atom, OR⁴ (R⁴ is as defined in claim 22) or ahydrocarbon group which may be optionally substituted by (1) a halogenatom, (2) a nitro group, (3) a cyano group, (4) a hydroxyl group, (5) alower alkyl group which may be halogenated, (6) a lower alkoxy group,(7) an amino group, (8) a mono-lower alkylamino group, (9) a di-loweralkylamino group, (10) a carboxyl group, (11) a lower alkylcarbonylgroup, (12) a lower alkoxycarbonyl group, (13) a carbamoyl group, (14) amono-lower alkylcarbamoyl group, (15) a di-lower alkylcarbamoyl group,(16) an arylcarbamoyl group, (17) an aryl group, (18) an aryloxy groupor (19) a lower alkylcarbonylamino group which may be optionallyhalogenated, or a salt thereof.
 30. A compound represented by theformula (Ia′):

wherein R^(1a) is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, or a carboxyl group which may be esterified oramidated; R^(2a) is unsubstituted, a hydrogen atom or a hydrocarbongroup which may be optionally substituted, R^(3ab) is a unsaturatedheterocyclic group containing 2 or less nitrogen atoms as the heteroatoms which may be optionally substituted, or an unsaturated monocyclicheterocyclic group containing a nitrogen atom and a sulfur atom as thehetero atoms; X^(a) is hydrogen, halogen, nitrile, a hydrocarbon groupwhich may be optionally substituted, a carboxyl group which may beoptionally esterified or amidated, an acyl group which may be optionallysubstituted, —NR^(4a)R^(5a), an oxygen atom, —OR^(4a), a sulfur atom, or—SR^(4a) (R^(4a) and R^(5a) are, respectively, a hydrogen atom, ahydrocarbon group which may be optionally substituted, or both may bindeach other to form a cyclic amino group or a heterocyclic group with thenitrogen atom bound thereto); bond portions indicated by both solid andbroken lines are either a single bond or a double bond, and bondportions indicated by a broken line are either a single bond orunsubstituted; ring B^(a) is a homocyclic or heterocyclic 5- to7-membered ring which may be optionally substituted; and m is an integerof 0 or 1, or a salt thereof.
 31. The compound according to claim 30,wherein R^(1a) and R^(2a) are, respectively, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group or an aryl group, each ofthe groups having 1 to 16 carbon atoms, or a salt thereof.
 32. Thecompound according to claim 30 or 31, wherein R^(3ab) is pyridinyl whichmay be optionally substituted by (1) a halogen atom, (2) a lower alkylgroup, (3) a cycloalkyl group, (4) a lower alkynyl group, (5) a loweralkenyl group, (6) an aralkyl group, (7) an aryl group, (8) a loweralkoxy group, (9) an aryloxy group, (10) a lower alkanoyl group, (11) anarylcarbonyl group, (12) a lower alkanoyloxy group, (13) anarylcarbonyloxy group, (14) a carboxyl group, (15) a loweralkoxycarbonyl group, (16) an aralkyloxycarbonyl group, (17) a carbamoylgroup, (18) a mono-, di- or tri-halogeno-lower alkyl group, (19) anamidino group, (20) an amino group, (21) a mono-lower alkylamino group,(22) a di-lower alkylamino group, (23) a 3- to 6-membered cyclic aminogroup which may optionally containing 1 to 3 atoms selected from oxygen,sulfur and nitrogen atoms as the hetero atoms as well as carbon atomsand a nitrogen atom, (24) an alkylenedioxy group, (25) a hydroxyl group,(26) a nitro group, (27) a cyano group, (28) a mercapto group, (29) asulfo group, (30) a sulfino group, (31) a phosphono group, (32) asulfamoyl group, (33) a monoalkylsulfamoyl group, (34) adialkylsulfamoyl group, (35) an alkylthio group, (36) an arylthio group,(37) a lower alkylsulfinyl group, (38) an arylsulfinyl group, (39) alower alkylsulfonyl group, or (40) an arylsulfonyl group, or a saltthereof.
 33. The compound according to any one of claims 30 to 32,wherein X^(a) is an oxygen atom or OR^(4a) (R^(4a) is a hydrogen atom ora hydrocarbon group which may be optionally substituted by (1) a halogenatom, (2) a nitro group, (3) a cyano group, (4) a hydroxyl group, (5) alower alkyl group which may be optionally halogenated, (6) a loweralkoxy group, (7) an amino group, (8) a mono-lower alkylamino group, (9)a di-lower alkylamino group, (10) a carboxyl group, (11) a loweralkylcarbonyl group, (12) a lower alkoxycarbonyl group, (13) a carbamoylgroup, (14) a mono-lower alkylcarbamoyl group, (15) a di-loweralkylcarbamoyl group, (16) an arylcarbamoyl group, (17) an aryl group,(18) an aryloxy group or (19) a lower alkylcarbonylamino group which maybe optionally halogenated) or a salt thereof.
 34. The compound accordingto any one of claims 30 to 33, wherein R^(3ab) is a nitrogen-containingaromatic heterocyclic group, and ring B^(a) is a benzene ring which maybe optionally substituted by (1) a halogen atom, (2) a hydrocarbon groupwhich may be optionally substituted, (3) an amino group which may beoptionally substituted, (4) an lower alkoxy group which may beoptionally substituted, (5) a lower alkylenedioxy group (6) an aryloxygroup, (7) a lower alkanoyl group, (8) an arylcarbonyl, (9) a loweralkanoyloxy group, (10) an arylcarbonyloxy group, (11) a carboxyl group,(12) a lower alkoxycarbonyl group, (13) an aralkyloxycarbonyl group,(14) a carbamoyl group, (15) a mono-, di- or tri-halogeno-lower alkylgroup, (16) an amidino group, (17) an amino group, (18) a mono-loweralkylamino group, (19) a di-lower alkylamino group, (20) a 3- to6-membered cyclic amino group which may contain 1 to 3 atoms selectedfrom the group consisting of oxygen, sulfur and nitrogen atoms as thehetero atom as well as carbon atoms and one nitrogen atom, (21) analkylenedioxy group, (22) a hydroxyl group, (23) a nitro group, (24) acyano group, (25) a mercapto group, (26) a sulfo group, (27) a sulfinogroup, (28) a phosphono group, (29) a sulfamoyl group, (30) amonoalkylsulfamoyl group, (31) a dialkylsulfamoyl group, (32) analkylsulfanyl group, (33) an arylsulfanyl group, (34) a loweralkylsulfinyl group, (35) an arylsulfinyl group, (36) a loweralkylsulfonyl group, or (37) an arylsulfonyl group, or a salt thereof.35. The compound according to any one of claims 30 to 34, wherein thecompound is,6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,3-methyl-1-(2-pyridinyl)-6-(trifluoromethyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,6-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,7-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,3-ethyl-6,7-difluoro-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,6,7-difluoro-3-methyl-1-(3-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,6,7-difluoro-3-methyl-1-(6-methyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one,6,7-difluoro-3-methyl-1-(6-phenyl-2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,5-fluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one,or 1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinoline-4-one, or asalt thereof.
 36. A process for producing a condensed pyrazolederivative represented by the formula (I′):

wherein, R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted, or acarboxyl group which may be optionally esterified or amidated; R² isunsubstituted, or a hydrogen atom or a hydrocarbon group which may beoptionally substituted; R³′ is an unsaturated heterocyclic groupcontaining only one nitrogen atom as the hetero atom, which may beoptionally substituted; X′, Y′, and Z′ are, respectively, hydrogen,halogen, nitrile, a hydrocarbon group which may be optionallysubstituted, a carboxyl group which may be optionally esterified oramidated, an acyl group which may be optionally substituted, —CON₃,—NR⁴R⁵, ═N—N═R⁴, —N₃, an oxygen atom, —OR⁴, a sulfur atom or —SR⁴ (R⁴and R⁵ are, respectively, a hydrogen atom, a hydrocarbon group which maybe optionally substituted, a heterocyclic group which may be optionallysubstituted, or both may bind each other to form a cyclic amino group ora heterocyclic group with the nitrogen atom bound thereto), or X′ and Y′may bind each other to form ring A, while either X′ or Z′ is an oxygenatom or —OR⁴; bond portions indicated by both solid and broken lines areeither a single bond or a double bond, and a bond portion indicated by abroken line is either a single bond or unsubstituted; and ring A iseither a homocyclic or heterocyclic 5- to 7-membered ring which may beoptionally substituted, or a salt thereof, which comprises subjecting acompound represented by the formula (IV):

wherein, R¹ is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, an amino group which may be optionallysubstituted, a thiol group which may be optionally substituted, or acarboxyl group which may be optionally esterified or amidated; R³′ is anunsaturated heterocyclic group containing only one nitrogen atom as thehetero atom, which may be optionally substituted; R′ is a hydrogen atomor a hydrocarbon group which may be optionally substituted; and Y′ andZ′ are, respectively, hydrogen, halogen, nitrile, a hydrocarbon groupwhich may be optionally substituted, a carboxyl group which may beoptionally esterified or amidated, an acyl group which may be optionallysubstituted, —CON₃, —NR⁴R⁵, ═N—N═R⁴, —N₃, an oxygen atom, —OR⁴, a sulfuratom or —SR⁴ (R⁴ and R⁵ are, respectively, a hydrogen atom, ahydrocarbon group which may be optionally substituted, a heterocyclicgroup which may be optionally substituted, or both may bind each otherto form a cyclic amino group or a heterocyclic group with the nitrogenbound thereto), or a salt thereof, to a cyclization reaction, and ifdesired, by subjecting the compound thus obtained, to a hydrolysisreaction, a protective group introduction reaction, a nitrilationreaction , an acylation reaction , an alkylation reaction, an oxidationreaction, a reduction reaction, a carbon chain elongation reaction, asubstituent exchange reaction and/or a deprotection reaction.
 37. Aprocess for producing the compound according to any one of claims 30 to34, which is represented by the formula (Ia″):

wherein, R^(1a) is a hydrogen atom, a hydrocarbon group which may beoptionally substituted, or a carboxyl group which may be optionallyesterified or amidated; and R^(3a) is an unsaturated heterocyclic groupcontaining 2 or less nitrogen atoms as the hetero atoms, which may beoptionally substituted, or a unsaturated monocyclic heterocyclic groupcontaining one nitrogen atom and one sulfur atom as the hetero atoms, mis an integer of 0 or 1, or a salt thereof, which comprises subjecting acompound represented by the formula (IIIa):

wherein, each symbol is as defined above, or a salt thereof, to areaction, in the presence of an acidic compound, with a2-oxocycloalkanecarboxylic ester represented by the formula (X):

wherein, R″ is a hydrocarbon group which may be optionally substituted,and ring B^(ab) is a 5- to 7-membered cycloalkane which may beoptionally substituted, or a salt thereof.
 38. A method for selectivelysuppressing Th2 immune responses, which comprises administrating acondensed pyrazole derivative represented by the formula (I):

wherein, each symbol is as defined in claim
 1. 39. Use of a condensedpyrazole derivative represented by the formula (I):

wherein, each symbol is as defined in claim 1, or a salt thereof forselectively suppressing Th2 immune responses.
 40. A method forinhibiting cyclooxygenase, which comprises administrating a condensedpyrazole derivative represented by the formula (I):

wherein, each symbol is as defined in claim 2, or a salt thereof. 41.Use of a condensed pyrazole derivative represented by the formula (I):

wherein, each symbol is as defined in claim 2, or a salt thereof, forinhibiting cyclooxygenase.